print
`ISSN 0030- 3755
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`Ophthalmologica
`223(6) 351-422 (2009)
`
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`223
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`6 09
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`ISSN 1423-0267
`
`www.karger.com/oph
`
`Ophthalmologica. Journal
`v. 223, no. 6 (2009)
`General Collection
`W1 OP337
`2009-12-01 11:06:01
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`PROPERlY OF THE
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`

`

` Review
`
` Ophthalmologica 2009;223:401–410
` DOI: 10.1159/000228926
`
` Received: December 11, 2008
` Accepted after revision: January 29, 2009
` Published online: July 20, 2009
`
` Emerging Pharmacologic Therapies for
`Wet Age-Related Macular Degeneration
`
` Zhang Ni a–c Peng Hui a–c
`
` a Department of Ophthalmology, First Affiliated Hospital of Chongqing Medical University, b Chongqing Key
`Laboratory of Ophthalmology, c Chongqing Eye Institute, Chongqing , PR China
`
` Key Words
` Age-related macular degeneration ⴢ Vascular epithelial
`growth factor ⴢ Choroidal neovascularization ⴢ
`Antiangiogenesis ⴢ Anti-inflammatory ⴢ Target therapy
`
` Abstract
` As researchers and clinicians are beginning to understand
`that wet age-related macular degeneration (AMD) is more
`than simply a vascular disease that includes angiogenic, vas-
`cular and inflammatory components, they are exploring
`new agents with different mechanisms of action addressing
`multiple targets in this complex pathophysiology. Some of
`them are already available in human trials or even approved
`vascular epithelial growth factor (VEGF) blockers such as
`Macugen, Lucentis, Avastin, VEGF Trap-Eye and Cand5; VEGF
`receptor blockers such as TG100801, vatalanib, pazopanib,
`Sirna-027 and a vaccine approach; inflammation inhibitors
`and
`immunosuppressants such as Retaane, Kenalog,
`ARC1905, POT-4, OT-551. The last group is mixed, containing
`agents such as Zybrestat, AdPEGF, Sirolimus, JSM6427,
`ATG003, E10030. This article reviews these currently emerg-
`ing agents and briefly discusses the next step for the treat-
`ment of wet AMD.
`Copyright © 2009 S. Karger AG, Basel
`
` Introduction
`
` One of the most common and poorly treated back-of-
`the-eye diseases is age-related macular degeneration
`(AMD). It is the leading cause of blindness in the devel-
`oped countries for people over 50 years [1] . The most se-
`vere form, wet AMD, accounts for 10% of cases, but 90%
`of the severe vision loss is associated with all AMD [2] . It
`is complicated by choroidal neovascularization (CNV),
`during which the choroidal new vessels invade the sub-
`retinal space through Bruch’s membrane to form fibro-
`vascular proliferative tissue containing vascular endo-
`thelial cells, fibroblasts, retinal pigment epithelial cells,
`and various inflammatory cells [3] . Retinal neurons are
`irreversibly damaged by lipid leakage and bleeding from
`the immature new vessels in the CNV tissue. Although
`molecular and cellular mechanisms are not fully eluci-
`dated, various efficacious target therapies are emerging
`and successful in human trials.
`
` Against VEGF
`
` Out of a panel of recently discovered and promising
`therapeutic targets, the most efficacious CNV treatment
`has relied on the vascular endothelial growth factor
`(VEGF). It is a subfamily of growth factors including
`members of VEGF-A, VEGF-B, VEGF-C, VEGF-D,
`
`Fax +41 61 306 12 34
`E-Mail karger@karger.ch
`www.karger.com
`
` © 2009 S. Karger AG, Basel
`0030–3755/09/2236–0401$26.00/0
`
` Accessible online at:
`www.karger.com/oph
`
` Peng Hui
` Department of Ophthalmology
` First Affiliated Hospital of Chongqing Medical University
` Chongqing 400016 (PR China)
` Tel. +86 23 8901 3056, E-Mail pengh9@yahoo.com.cn
`
`Mylan Exhibit 1075
`Mylan v. Regeneron, IPR2021-00880
`Page 3
`
`

`

`VEGF-E and placenta growth factor [4] . They are impor-
`tant signalling proteins involved in vasculogenesis, an-
`giogenesis and vascular permeability. VEGF-A is the
`most important member which is up-regulated by hy-
`poxia. It has been shown to stimulate endothelial cell mi-
`togenesis and cell migration. It is also a vasodilator that
`increases microvascular permeability. There are multiple
`isoforms of VEGF-A including VEGF-A 121 , VEGF-A 145 ,
`VEGF-A 148 , VEGF-A 162 , VEGF-A 165 , VEGF-A 183 , VEGF-
`A 189 and VEGF-A 206 (classified by amino acid number)
` [5] , of which VEGF-A 121 and VEGF-A 165 are the most
`abundantly expressed isoforms in the retina [6] .
`
` Macugen (Pegaptanib Sodium 0.3 mg; Eyetech/Pfizer)
` Pegaptanib [7] is a 28-base ribonucleic acid aptamer,
`covalently linked to two branched 20-kDa polyethylene
`glycol moieties to increase residency time within the eye
`following intravitreal injection (IVT). It selectively binds
`to the VEGF-A 165 , which is the most potent and prevalent
`isoform expressed during pathologic neovascularization
` [8] . Macugen was approved by the Food and Drug Ad-
`ministration (FDA) in December 2004 for the treatment
`of wet AMD [9] , becoming the first pharmacological
`agent approved for ocular angiogenesis.
` Its efficacy and safety were confirmed by a pivotal
`phase III trial VISION [7] , in which 1,208 patients with
`all CNV subtypes secondary to AMD received Macugen
`IVT or sham injections every 6 weeks for 48 weeks. The
`results demonstrated that 70% of Macugen-treated pa-
`tients lost fewer than 15 letters compared with 55% of
`sham-treated patients at 12 months (p ! 0.001). Among
`the adverse events that occurred, endophthalmitis (1.3%),
`traumatic injury to the lens (0.7%), and retinal detach-
`ment (0.6%) were the most serious that have been report-
`ed and required vigilance.
`
` Lucentis (Ranibizumab 0.5 mg; Genentech/Novartis
`Ophthalmics)
` Ranibizumab is a 48-kDa humanized monoclonal an-
`tibody fragment that neutralizes and inhibits all known
`forms of VEGF-A, including their protein degradation
`products [10] . It was approved by FDA in June 2006 for
`the treatment of wet AMD [11] .
` In a pivotal clinical trial, MARINA [10] , 716 patients
`with minimal classic or occult CNV secondary to AMD
`were treated with a 0.3- or 0.5-mg dose of Lucentis IVT
`or sham injections monthly. The results demonstrated
`that 94.5 and 94.6% of Lucentis-treated patients lost few-
`er than 15 letters (0.3 and 0.5 mg, respectively), compared
`with 62% of sham-treated patients after 12 months. What
`
`is more, the Lucentis-treated patients gained an average
`of 6.5 and 7.2 letters of visual acuity (VA), whereas the
`sham-treated patients lost an average of 10.4 letters (p !
`0.001 for each comparison).
` The results of another pivotal clinical trial, ANCHOR
` [12] , were very similar; 423 patients with predominantly
`classic CNV secondary to AMD were treated with a 0.3-
`or 0.5-mg dose of Lucentis IVT monthly and sham pho-
`todynamic therapy (PDT) or sham injection and PDT ev-
`ery 3 months. 94.3 and 96.4% of Lucentis-treated patients
`lost fewer than 15 letters compared with 64.3% of PDT-
`treated patients. Mean VA increased by 8.5 letters and
`11.3 letters in the Lucentis-treated patients compared
`with a decrease of 9.5 letters in the PDT-treated patients
`(p ! 0.001 for each comparison).
` These two trials, as well as the other key trials, PIER
` [13] , FOCUS [14] and SAILOR [15] , suggested that the
`treatment of Lucentis IVT is well tolerated and effica-
`cious. More recently, the study HORIZON [16] supported
`the long-term safety of Lucentis. It is a phase III extension
`study allowing patients completing the trials MARINA,
`ANCHOR and FOCUS to continue to receive Lucentis
`less frequent ‘as needed’, but patients on average had a
`5.3-letter decline in VA with 3–4 injections over the en-
`tire year, suggesting that monthly dosing may be better
`in some patients.
`
` Avastin (Bevacizumab, 1.25 mg; Genentech/Novartis
`Ophthalmics)
` Avastin [17] is a 149-kDa humanized full-length
`monoclonal antibody which is approximately 3 times
`larger than Lucentis and is capable of inhibiting all iso-
`forms of VEGF-A. It was FDA approved in February 2004
`for the treatment of metastatic colon cancer, but was not
`yet originally approved for ocular disease [18] . In spite of
`this, as there were several uncontrolled studies [19, 20] on
`wet AMD showing that Avastin IVT may be efficacious
`and safe, also at much lower cost than Lucentis, it is used
`as off-label drug to treat patients with wet AMD and mac-
`ular edema.
` Recently, the result of a small study [21] comparing
`Lucentis and Avastin monotherapy in 46 patients for the
`treatment of wet AMD has shown that Lucentis has a
`slight advantage over Avastin. But due to the small num-
`ber of patients and the retrospective nature of this analy-
`sis, conclusions should be made with caution.
` What is desperately needed is a larger head-to-head
`comparison of the efficacy and adverse consequences be-
`tween Avastin and Lucentis or Macugen. A randomized
`phase II trial, MAAM [22] , comparing Avastin and Ma-
`
`402
`
`Ophthalmologica 2009;223:401–410
`
` Ni/Hui
`
`Mylan Exhibit 1075
`Mylan v. Regeneron, IPR2021-00880
`Page 4
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`

`

`cugen IVT in 60 patients with wet AMD is under way and
`will soon be finished. Another ongoing clinical trial is
`CATT [23] . It is a phase III trial comparing Avastin and
`Lucentis IVT in 1,209 patient with wet AMD. If the trials
`demonstrate equivalence between these two drugs this
`would allow more affordable and widespread use of anti-
`VEGF therapy.
`
` VEGF Trap-Eye (Regeneron)
` VEGF Trap-Eye [24] is a 110-kDa recombinant protein
`with the binding portions of VEGF receptors (VEGFR)
`VEGFR-1 and VEGFR-2 fused to the Fc region of human
`IgG that binds all forms of VEGF-A, placenta growth fac-
`tor and VEGF-B with a very high affinity (about 140
`times that of Lucentis).
` In a phase I trial (CLEAR) AMD-1 was administered
`intravenously for the treatment of CNV. The investiga-
`tors found a dose-dependent decrease in the central reti-
`nal thickness, as well as a dose-dependent increase in sys-
`temic blood pressure with a maximum tolerated dose of
`1 mg/kg. Since then, systemic VEGF Trap-Eye was halt-
`ed, only IVT is being evaluated for ocular disease [25] .
` Recently, the result of CLEAR IT-2 [26] was released.
`In this phase II trial, patients were initially treated with
`either fixed monthly or quarterly doses for 12 weeks and
`then continued to receive treatment for another 40 weeks
`on a PRN (as needed) dosing schedule. It demonstrated
`up to 9 mean letters gained in VA and up to 161 ␮ m re-
`duction in central retinal thickness at 52 weeks (p !
`0.0001). The patients received on average only two addi-
`tional injections over 40 weeks after a 12-week fixed dos-
`ing period. It was generally well tolerated, and there were
`no drug-related serious adverse events.
` After these positive initial results, it is reasonable to
`take VEGF Trap-Eye into phase III clinical trials VIEW1
` [27] and VIEW2 [28] , which are ongoing to compare with
`Lucentis in 2,400 patients with wet AMD in the US, Eu-
`rope, Asia, Japan, Australia and South America. These
`global clinical programs will provide additional data to
`further evaluate the efficacy and safety of VEGF Trap-
`Eye.
`
` Cand5 (Bevasiranib; OPKO Health)
` Cand5 [29] is a small interfering mRNA working by
`shutting down the mRNA specific to the genes that en-
`code for the production of VEGF-A; it therefore inhibits
`CNV, but has no effect on residual VEGF in the eye.
` In a phase I dose-escalation study [30] in 15 patients
`with wet AMD, Cand5 was found to be safe and well tol-
`erated at doses up to 3.0 mg over a 6-week period, and the
`
`investigators concluded that Cand5 did not escape the
`eye to the systemic circulation.
` During a phase II randomized study of trial CARE
` [29] , 129 patients with classic or active minimally classic
`AMD, including those patients who had failed previous
`treatments, received multiple Cand5 IVT of 3 doses over
`6 months. The results showed that the average time to
`rescue (need for another injection) in patients given the
`lowest dose (0.2 mg) was 153 days [31]. Patients who re-
`ceived higher doses (1.5 and 3 mg) had an average time to
`rescue that was much longer.
` Due to its different mechanisms of action, compared
`to the other anti-VEGF agents, researchers considered
`that combining Cand5 with a VEGF-binding agent might
`offer a better response. Therefore, a phase III clinical tri-
`al, CARBON [32] , is under way that will compare the ef-
`ficacy of Cand5 administered every 8 weeks or 12 weeks
`after an initial pretreatment with 3 injections of Lucentis
`versus Lucentis monotherapy every 4 weeks in patients
`with wet AMD.
`
` Against VEGFR and PDGFR
`
` VEGFR mediate the biological functions of the VEGF
`family. They consist of three protein-tyrosine kinases
`(VEGFR-1, VEGFR-2, and VEGFR-3) and two non-pro-
`tein kinase coreceptors (neuropilin-1 and neuropilin-2)
` [33] . VEGFR-2 appears to mediate almost all of the known
`cellular responses to VEGF; the role of VEGFR-1 has been
`characterized as a decoy receptor evolved to trap free
`VEGF-A, that prevents continuous VEGFR-2 activation
` [34] . Platelet-derived growth factor is a growth factor
`which has been demonstrated to stimulate angiogenesis
`and pericyte recruitment [35] . Loss of pericytes in retinal
`vessels is thought to be associated with abnormalities and
`instability of vasculature, including the formation of mi-
`croaneurysms and vascular permeability, and it was also
`thought to be associated with regression of maturing
`neovascularization [36, 37] . Therefore, inhibition of
`VEGFR and platelet-derived growth factor receptor
`(PDGFR) seems to be another approach to prevent
`CNV.
`
` TG100801 (TareGen)
` TG100801 is a potent tyrosine kinase inhibitor and
`a prodrug administration of TG100572, which binds
`VEGFR and PDGFR and inhibits their activity [38] . Data
`have suggested that the delivery of the agent occurs by lo-
`cal penetration through the sclera rather than by system-
`
` Treatment for Wet Age-Related Macular
`Degeneration
`
`Ophthalmologica 2009;223:401–410
`
`403
`
`Mylan Exhibit 1075
`Mylan v. Regeneron, IPR2021-00880
`Page 5
`
`

`

`ic absorption, as neither compound was detectable in the
`plasma [38] . For reasons of noninvasiveness, it is used as
`an eye drop.
` A phase I trial [39] , using low and high doses applied
`topically twice daily for 14 days in 42 healthy volunteers,
`was completed and showed good tolerance. A phase II
`randomized study [40] is ongoing to evaluate the efficacy
`and safety of dosing with two dose levels of TG100801. It
`will be good news if these eye drops work, as this route of
`administration would be more suited for prophylaxis in
`AMD patients who are at risk of progressing to CNV.
`
` Vatalanib (PTK787; Novartis)
` Vatalanib [41] is another potent tyrosine kinase inhib-
`itor with good oral bioavailability and activity against the
`VEGFR family, PDGFR ␤ and c-Kit receptor kinases. Pre-
`clinical studies [41] suggest that vatalanib induces dose-
`dependent inhibition of VEGF-induced angiogenesis. A
`phase I/II trial, ADVANCE [42] , to evaluate the safety
`and efficacy of oral vatalanib combined with PDT with
`verteporfin in 50 patients has been completed, but the
`data have not yet been published in a peer-reviewed jour-
`nal.
`
` Pazopanib (GW786034; GlaxoSmithKline)
` Pazopanib [43] is a second-generation multitargeted
`tyrosine kinase inhibitor against all VEGFR, PDGFR ␣ ,
`PDGFR ␤ , and c-kit. A phase I clinical trial using pazo-
`panib as eye drops in 38 healthy volunteers has success-
`fully demonstrated its safety and tolerability. Subsequent-
`ly, a phase II trial [44] to evaluate its pharmacodynamics,
`pharmacokinetics and safety is currently recruiting pa-
`tients.
`
` Sirna-027/AGN211745 (Allergan)
` Sirna-027 [45] is a chemically stabilized small inter-
`fering mRNA (siRNA) designed to silence the gene for
`VEGFR-1 so that it is unable to translate the message to
`increase vascular production.
` The investigators estimated that Sirna-027 has a long-
`lasting effect on VA after a single-dose IVT. A phase I
`study [46] evaluated a single Sirna-027 IVT ranging from
`100 to 1,600 mg in 26 patients with wet AMD. Three
`months after the single injection, 24 patients (92%)
`showed VA stabilization, with 4 patients (15%) experienc-
`ing clinically significant improvement in VA.
` At present, investigators are in a phase II randomized
`study [47] that evaluates the safety and efficacy of Sirna-
`027 IVT in comparison with Lucentis in 135 patients with
`wet AMD.
`
` Anti-VEGFR Vaccine Therapy
` This is an immunologic approach to combat CNV. A
`recent report demonstrated CD8+ cytotoxic T lympho-
`cyte (CTL)-mediated regression of physiologic and patho-
`logic retinal new vessels [48] , thus a hypothesis of a pos-
`sible immunologic therapy for CNV by inducing CTL re-
`sponses targeting a specific molecule highly expressed in
`CNV-associated endothelial cells was raised. It was ap-
`proved by a study [49] using an animal model which first
`showed that CNV can be reduced by inducing cellular
`immunity specific for VEGFR-2.
` More recently, a phase I study [50] of anti-VEGFR vac-
`cine therapy has been recruiting participants. The pa-
`tients will be vaccinated once a week for 12 weeks. On
`each vaccination day, VEGFR-1 peptide (1 mg) and
`VEGFR-2 peptide (1 mg) mixed with Montanide ISA 51
`will be administered by subcutaneous injection. This
`study will evaluate the safety and tolerability as well as
`the immunological and clinical response of the vaccine
`therapy to treatment of wet AMD and neovascular macu-
`lopathy.
`
` Against Inflammatory and Immune-Mediated
`Events
`
` Studies strongly suggested that the process of drusen
`formation includes inflammatory and immune-mediat-
`ed events, especially in the progression from dry to wet
`AMD.
` A previous study [51] suggested that drusen include
`remnants of the retinal pigment epithelium, dendritic
`cell processes, and a variety of immune-associated mol-
`ecules including immunoglobulins, class II antigens, and
`a host of complement components, activators, and regu-
`lators. The observations led the investigators to conclude
`that AMD, like other age-related diseases, could involve
`a major inflammatory component. Another report [52]
`has documented macrophages as the predominant type
`of leukocytes involved in CNV. An earlier study [53]
`demonstrated that lymphocytes, fibroblasts, and myofi-
`broblasts may also play a role. Therefore, by inhibiting
`immune and inflammatory responses, therapeutic ben-
`efit may be achieved in both dry and wet AMD.
`
` Retaane 15 mg (Anecortave Acetate Suspension,
`15 mg; Alcon)
` Retaane [54, 55] is an analog of cortisol acetate that
`inhibits multiple steps within the angiogenic cascade,
`both upstream and downstream of angiogenic growth
`
`404
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`Ophthalmologica 2009;223:401–410
`
` Ni/Hui
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`factor ligand-receptor interaction. It is administered with
`a special blunt-tipped cannula used to deliver a periocu-
`lar posterior juxtascleral depot onto the outer surface of
`the sclera once every 6 months. In September 2007, Alcon
`received an approvable letter from FDA for Retaane in the
`treatment of wet AMD; however, the FDA will require an
`additional clinical trial before it grants final approval
` [56] .
` A 6-month study [57] involving 136 patients evaluated
`Retaane (15 or 30 mg) versus placebo following initial
`treatment with PDT. The Retaane-treated patients main-
`tained better VA than placebo-treated patients. In a 2-
`year phase III trial comparing Retaane with PDT in 530
`patients with predominantly classic subfoveal CNV sec-
`ondary to AMD, the proportion of patients losing less
`than 3 lines of vision in the Retaane and PDT groups were
`45 and 49%, respectively (p = 0.43, not statistically differ-
`ent). The study demonstrated the safety and efficacy for
`the treatment of wet AMD with either the drug or the
`posterior juxtascleral depot administration procedure.
`
` Kenalog (Triamcinolone Acetonide, 40 mg/ml;
`Schering-Plough)
` Kenalog is known as a corticosteroid hormone that
`has a multitude of anti-inflammatory effects and also
`seems to have direct antiangiogenic properties. It has
`been used as an off-label drug for the treatment of wet
`AMD over the last several years.
` Results at 1 year following a single IVT in a prospec-
`tive randomized trial [58] did not support the use of Ken-
`alog IVT as a monotherapy for wet AMD. Subsequently,
`to reduce subretinal edema and the burst of VEGF pro-
`duced immediately after PDT [59] , use of Kenalog IVT
`with PDT has become common practice with approved
`efficacy.
`
` POT-4 (Potentia Pharmaceuticals)
` POT-4 [60] is a peptide capable of binding to human
`complement factor C3 (C3). As C3 is a central component
`of all known complement activation pathways, its inhibi-
`tion effectively shuts down all downstream complement
`activation that could otherwise lead to local inflamma-
`tion, tissue damage and up-regulation of angiogenic fac-
`tors such as VEGF.
` A phase I single escalating dose study [61] has just re-
`leased its first results, which indicate that POT-4 IVT is
`safe, and the data accumulated so far support the contin-
`ued investigation of POT-4 for the treatment of both dry
`and wet AMD with a larger randomized phase II trial to
`further define its efficacy profile.
`
` ARC1905 (Ophthotech Corp.)
` ARC1905 [60] is an anti-C5 aptamer, which prevents
`the formation of key terminal fragments (C5a and C5b-9)
`by inhibiting human complement factor C5 (C5). C5a
`fragment is an important inflammatory activator induc-
`ing vascular permeability, recruitment and activation of
`phagocytes. C5b-9 is involved in the formation of mem-
`brane attack complex (C5b-9), which initiates cell lysis
` [60] . Thus by inhibiting these C5-mediated inflamma-
`tory, ARC1905 might be beneficial in wet AMD.
` A phase I study [62] to evaluate the safety, tolerability,
`and pharmacokinetic profile of multiple doses of ARC1905
`IVT in combination with multiple doses of Lucentis is
`currently in progress.
`
` OT-551 (Othera)
` OT-551 [63] , an antiangiogenic drug in eye drop form,
`operates within the cell to down-regulate nuclear factor
`kappa B, which is an important transcription factor com-
`plex playing a fundamental role in the regulation of acute
`inflammation through activating the cytokine cascade
`and production of other pro-inflammatory mediators
` [64] .
` A phase I trial [63] demonstrated that when the com-
`pound is added to Lucentis or Avastin treatment, there is
`a synergistic effect in patients with wet AMD. At present,
`two phase II studies [65, 66] for dry AMD are under
`way.
`
` Others
`
` Zybrestat (Combretastatin A4 Phosphate/CA4P;
`OXiGENE)
` The antimitotic agent CA4P [67] is a water-soluble
`prodrug of combretastatin A4 that was originally isolated
`from the tree Combretum caffrum . Histological and im-
`munohistochemical analysis indicated that CA4P causes
`changes in shape, cytotoxicity and apoptosis of prolifer-
`ating endothelial cells, but not of quiescent cells; it per-
`mits the development of normal retinal vasculature while
`inhibiting aberrant neovascularization [68, 69] .
` A phase I/II trial [70] in 15 patients with wet AMD us-
`ing intravenous CA4P administration once a week for 4
`weeks with a 6-month follow-up demonstrated that CA4P
`had been well tolerated up to doses of 36 mg/m 2 and the
`side effects observed were increased blood pressure below
`clinical significance. Positive results were also reported
`in a phase II study [71] in patients with CNV associated
`with myopic macular degeneration.
`
` Treatment for Wet Age-Related Macular
`Degeneration
`
`Ophthalmologica 2009;223:401–410
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`Table 1. Summary
`
`Agent
`
`Phase1 Property
`
`Target
`
`Classifi-
`cation
`
`Against
`VEGF
`
`Against
`VEGFR
`and
`PDGFR
`
`Against
`inflam-
`matory
`and
`immune
`events
`Others
`
`Macugen (pegaptanib)
`Lucentis (ranibizumab)
`
`Avastin (bevacizumab)
`VEGF Trap-Eye
`
`Cand5 (bevasiranib)
`TG100801
`vatalanib (PTK787)
`pazopanib (GW786034)
`
`Sirna-027 (AGN211745)
`vaccine therapy
`Retaane (anecortave acetate)
`Kenalog (triamcinolone
`acetonide)
`ARC1905
`POT-4
`OT-551
`Zybrestat (CA4P)
`AdPEDF
`JSM6427
`ATG003
`Sirolimus (rapamycin)
`E10030
`
`IV
`IV
`
`III
`III
`
`III
`II
`I/II
`II
`
`II
`I
`III
`III
`
`I
`I
`II
`II
`I
`I
`II
`II
`I
`
`Route
`
`IVT
`IVT
`
`IVT
`IVT
`
`IVT
`eye drop
`oral
`eye drop
`
`IVT
`IH
`PJD
`IVT
`
`ribonucleic acid aptamer (50 kDa) VEGF-A165 isoform
`monoclonal antibody
`all VEGF-A isoforms
`fragment (48 kDa)
`monoclonal antibody (149 kDa)
`decoy receptor (110 kDa)
`
`small interfering mRNA
`tyrosine kinase inhibitor
`tyrosine kinase inhibitor
`tyrosine kinase inhibitor
`
`small interfering mRNA
`inducing CTL responses
`steroid
`steroid
`
`all VEGF-A isoforms
`all VEGF-A isoforms and
`VEGF-B, PIGF
`VEGF-A mRNA
`VEGFR, PDGFR
`VEGFR, PDGFR␤, c-kit
`all VEGFR, PDGFR␣,
`PDGFR␤, c-kit
`VEGFR-1
`VEGFR-1, VEGFR-2
`inhibits proteolytic cascade
`inhibits proteolytic cascade
`
`anti-C5 aptamer
`C3 inhibitor
`free radical scavenger
`analogue of colchicine
`adenoviral PEDF
`integrin ␣5␤1-antagonist
`mecamylamine (nACh receptor)
`macrolide
`three compounds (an aptamer +
`ARC1905 + volociximab)
`
`complement factor C5
`complement factor C3
`nuclear factor kappa B
`vascular disruption
`PEDF
`integrin ␣5␤1
`nicotinic acetylcholine (nACh)
`mTOR/Akt
`PDGF-B, integrin ␣5␤1, C5
`
`IVT
`IVT
`oral
`oral
`IVT
`IVT
`eye drop
`ISC IVT
`oral
`
`PIGF = Placenta growth factor; mTOR = mammalian target of rapamycin; ISC = subconjunctival injection; IH = hypodermic
` injection; PJD = periocular posterior juxtascleral depot.
`1 Phase of FDA-mandated clinical trials.
`
` Believing that it is feasible to deliver CAP4 topically,
`OXiGENE Co. is currently advancing the development of
`a topical formulation of CA4P for ophthalmological dis-
`eases.
`
` AdPEDF (GenVec)
` Pigment epithelium-derived factor (PEDF) is one of
`the most potent antiangiogenic proteins found in hu-
`mans, which were shown to inhibit VEGF-induced pro-
`liferation, migration of microvascular endothelial cells,
`reduce VEGF-induced hypermeability and cause vessel
`regression in established neovascularization [72, 73] .
`AdPEDF uses GenVec’s proprietary adenovector, a DNA
`carrier, to deliver the PEDF gene, resulting in the local
`production of AdPEDF in the treated eye. It is currently
`under development for the treatment of wet AMD.
`
` A phase I escalating-dose clinical trial [74] in 28 pa-
`tients with advanced wet AMD was completed. Three to
`six months after a single injection, it suggested that 50–
`94% of patients had a stabilization or improvement in le-
`sion size from baseline, suggesting that antiangiogenesis
`may last for several months after a sing