`
`Anti-VEGF drugs in the
`prevention of blindness
`
`David Yorston
`Consultant Ophthalmologist: Tennent
`Institute of Ophthalmology, Gartnavel
`Hospital, Glasgow, UK.
`dbyorston@btinternet.com
`
`Disorders of the blood vessels in the
`retina are responsible for some of the
`most commoncausesofblindness in the
`world. These include:
`
`* retinopathy of prematurity (an important
`cause of blindness in children in middle-
`income countries)
`* diabetic retinopathy (the most common
`cause of blindness in the working-age
`population of industrialised countries)
`* age-related macular degeneration (the
`third most commoncause ofblindness
`in the world).
`
`All of these conditions are causedpartly
`by over-production of a protein called
`vascular endothelial growth factor
`(VEGF). This protein was discovered in
`the 1980sandis importantin the growth
`and developmentof blood vessels. VEGF
`productionis increased by hypoxia (a lack
`of oxygen). So, if a tissue is not getting
`enough oxygen, it will produce more
`VEGF, which will stimulate the growth of
`additional blood vessels to provide more
`oxygen. This is beneficial in the heart
`muscle,or in a growing baby; however,in
`the eyeit can be harmful.
`The effects of VEGF may be summa-
`rised as:
`
`* Increased permeability of existing blood
`vessels, causing them to leak.
`* Growth of new blood vessels, which may
`bleed orleakfluid and proteins.
`
`In the eye, both canlead toretinal
`damage.
`Normal retinal capillaries (very fine
`blood vessels in the retina) are sealed
`thanks to tight junctions between the
`cells making up the capillary walls. This
`meansthat large molecules, such as
`proteins andlipids, cannot leak out of
`theseretinal capillaries into the retina. In
`the presenceof excessive VEGF, however,
`the capillaries start to leak and large
`molecules form exudates and escape into
`the retina, causing oedemain the
`surroundingtissues. If this affects the
`macula, then the centralvision will be
`reduced. This is what causes diabetic
`macular oedema.
`Excessive VEGF also causes the growth
`of new, abnormalretinal blood vessels
`and capillaries. These do not grow within
`the retina, where they might be useful.
`
`Instead, the abnormal capillaries grow out
`from the retina onto the surface of the
`vitreous, where the vitreous touches the
`retina. This happensin proliferative
`diabetic retinopathy and retinopathy of
`prematurity. The new vessels arefragile
`and proneto tearing. When a newvessel
`is tom, it bleeds, causing vitreous
`haemorrhage.As the vitreous contracts,
`the new vessels pull on the retina,
`causing a traction retinal detachment.If
`the detachmentincludes the macula,
`vision will be impaired.
`In the presence of excessive VEGF, new
`vessels can also grow out from the choroid
`(the layer immediately underthe retina).
`These newvessels grow into the space
`betweenthe retina and the choroid,
`usually just underthe retinal pigment
`epithelium. The new vessels leak exudates
`formed offluid or blood, causing oedema;
`eventually a fibrous scar is formed that
`destroys the photoreceptorcells at the
`centre of the macula. This is what
`happensin exudative(or ‘wet’) age-related
`macular degeneration (AMD).
`Because of these very damaging
`effects in the eye, researchers have been
`workingfor years to find a way to block the
`activity of VEGFin the eye.
`
`Anti-VEGF drugs
`VEGF has many beneficial effects in the
`rest of the body. Therefore, any
`anti-VEGF drug hasto be given by a route
`that gives the maximum effect in the eye,
`but little or no effect elsewhere. In
`
`practice, this meansit must be injected
`into the eye (intraocularinjection). This
`carries a number ofrisks, and it is
`thought that about 1 in every 1,000
`injections has a serious complication
`suchas cataract, vitreous haemorrhage,
`retinal detachment,or infection. Each
`injection must be handled with appro-
`priate sterilisation and aseptic technique
`(see page 47).
`The two mostwidely used drugs at
`present are Lucentis (ranibizumab) and
`Avastin (bevacizumab). Both drugs are
`monoclonalantibodiesthat bind to all
`three forms of VEGF. Theyare very similar
`drugs (see page 48), but Lucentis is a
`smaller molecule andis believed to bind
`VEGF in the eye with greateraffinity.
`Lucentis is intended purely for intraocular
`injection, and each vial can only be used
`for one patient. Avastin was intended to
`be given intravenously as an anti-cancer
`drug, and comesin vials of 100 mg.
`As the doserequired for intravitreal
`
`injection is only 2.5mg, onevial of LOO mg
`of Avastin can be usedto treat 40
`
`patients, provided that you have the
`necessary skills and facilities to prepare
`sterile injections for intraocularinjection.
`In the United Kingdom, the British
`National Formulary gives a netprice of
`£242" fora 100 mgvialof Avastin,
`(containing 40 doses). The British
`National Formulary gives a netprice of
`£742" for a single 2.5 mg dose of
`Lucentis. This meansthat a single dose of
`Avastin can workout to be over 100 times
`cheaperthan a single dose of Lucentis
`(provided that you have theskills and
`facilities, as stated above). ["Note: The
`actualprices of drugs vary considerably
`due to local purchasing arrangements,
`and maybevery different from the net
`prices quoted above. These are taken
`from the British National Formulary, and
`only give anindication of the relative costs
`of the drugs.]
`The most recently approved drugis
`aflibercept (also known as Eylea). Thisis
`an artificial protein that contains the VEGF
`receptor moleculesthat are normally
`attached to cell membranes. The VEGF
`
`binds to these receptors andis trapped
`and rendered harmless.Aflibercept
`seemsto be as effective as Avastin and
`Lucentis, but may be given less frequently.
`In the British National Formulary, a single
`dose hasa netprice of £816.
`
`Side-effects
`
`VEGFis important for the growth of new
`blood vessels. Although the dose of
`anti-VEGF neededto treat eye diseasesis
`very small, it has been shown to reduce
`the level of VEGF in the bloodstream. This
`meansthatthereis a theoretical risk that,
`in adults, anti-VEGF drugs mayincrease
`the risk of cardiovascular disease,
`including heart attacks and strokes.
`However, clinical trials have not shown
`conclusive evidenceof an increased risk
`of cardiovascular disease in patients
`treated with anti-VEGF drugs compared to
`those given sham injections.
`In babies and young children, VEGF is
`essential for the growth of blood vessels
`and normal growth and developmentof
`manyotherorgansincluding the lungs,
`kidney andbrain. This is one of the
`reasons whyanti-VEGF drugs are
`absolutely contra-indicated in pregnancy.
`Womenofchildbearing age should have a
`pregnancytestpriorto starting treatment,
`and mustavoid pregnancy during
`treatment. Although Avastin has been
`
`44 “©\COMMUNITY EYE HEALTH JOURNAL | VOLUME 27 ISSUE 87 | 2014
`
`Mylan v. Regeneron, IPR2021-00881
`
`U.S. Pat. 9,254,338, Exhibit 2271
`
`Exhibit 2271
`Page 01 of 03
`
`

`

`
`Use of anti-VEGF drugs at the Instituto de
`la Vision de Montemorelos
`Pedro A Gomez Bastar
`CBM MedicalAdviser and Chairman,Instituto de la Vision, Universidad de
`Montemorelos, Mexico pgomez07@gmail.com
`
` s
`
`:E8<2 8
`
`di
`
`1 Whichanti-
`VEGF agents
`do we use?
`Weuse bevazucimab
`(Avastin) — the dose
`used is 2.5 mg (0.1 ml).
`This anti-VEGF agentis
`used because of its:
`
`* proven efficacy and
`effectiveness (CATT &
`IVAN studies)
`* lowcost, makingit
`affordable for our
`patients.
`
`Anti-VEGFinjections are given in a clean room
`
`2 Whatare the
`indications?
`¢ Vitreous haemorrhage secondary to
`proliferative diabetic retinopathy —
`particularly when there has been no
`previouslaser.
`* Prior to vitrectomyforproliferative
`diabetic retinopathy.
`* Clinically significant macular oedema
`dueto diabetic retinopathy.
`¢ Macular oedema secondary to branch
`or centralretinal vein occlusion.
`° Exudative age-related macular
`degeneration.
`¢ Neovascular glaucoma.
`
`3 Whogives the
`injections?
`Intra-vitreal injections are always given
`by an ophthalmologist, for example:
`
`* retina specialists
`* retina subspecialty trainees
`* ophthalmology residents in theretinal
`service.
`
`4 Are anti-VEGF agents
`used without OCT?
`Anti VEGF agents are used without OCT
`in selected cases:
`
`* vitreous haemorrhage secondary to
`proliferative diabetic retinopathy —
`particularly when there has been no
`previous laser
`* priorto vitrectomyforproliferative
`diabetic retinopathy
`* clinically significant macular oedema
`dueto diabetic retinopathy
`* neovascular glaucoma.
`
`5 What are the outcomes?
`Clinical experience has been very
`positive and webelievethis is a cost-
`effective treatmentfor our patients.
`
`Vitreous haemorrhage secondary
`to proliferative diabetic retinopathy:
`Wehave beenpleasedwith our results.
`Anti-angiogenic therapy reduces the
`vitreous haemorrhage in many
`patients with diabetic retinopathy,
`allowingusto apply laser and avoid
`vitrectomy surgery.
`
`Prior to vitrectomyforproliferative
`diabetic retinopathy: Application
`3-5 days before surgery reduces the
`risk of intra-operative and post-
`operative bleeding.
`
`Neovascular glaucoma:In these
`patients, we are careful to avoid further
`increases in the IOP. Whentherubeosis
`regresses we apply pan-retinallaser,
`giving us more controloftheiris
`neovascularisation.
`
`Clinically significant macular
`oedema:In clinically significant macular
`oedemadueto diabetic retinopathy, we
`normally apply three doses of Avastin
`with 1-monthintervals betweeninjec-
`tions. After the last injection, a macular
`OCTis requested and,if the oedema
`has decreased, we apply focallaser.
`
`Age-related macular degeneration
`(AMD): In patients with exudative AMD,
`aninjection is given every month for
`several months to improve visual acuity
`and to control the disease,following the
`‘treat and extend’ protocol.
`
`7€~ COMMUNITY EYE HEALTH JOURNAL| VOLUME 27 ISSUE 87 | 2014 45
`
`used in the managementof retinopathy of
`prematurity, its use is controversial,
`becauseof the potential for serious
`adverse effects when usedin young
`babies (see panel on page 46).
`In practice, the major adverse effects
`of these drugs appearto be associated
`withthe intraocularinjection rather than
`the active drug.
`
`Treatment regimesin adults
`Regardless of the treatmentindication,
`there are essentially two regimes for
`administering anti-VEGF drugs:
`continuous and intermittent/as
`required (or pro re nata, PRNfor short).
`Mostof theinitial trials were done as
`
`a continuous regime,with regular
`monthly injections over the course of 2
`years,i.e. patients would have 24injec-
`tions in total. These trials showed that
`treatmentdelivered in this way was
`effective, but it is also expensive and
`inconvenientfor both the patient and the
`health care provider.
`A numberofothertrials have examined
`PRN regimes. These areallfairly similar
`and consist of three injections given over
`3 months,followed by review. At this point
`the patient may:
`
`* be much better, in which case no
`additional treatment is needed
`* have no improvementatall, in which
`case further treatmentis futile
`* have some improvement, which would
`justify further injections.
`
`Even among those patients who do very
`well, and do not require more than three
`injectionsinitially, manywill relapse and
`require furtherinjections in the future.
`This meansthey mustbe regularly
`reviewed in the clinic, i.e. every 1-2
`months,whichinvolvestesting of visual
`acuity and/orretinal thickness.If patients’
`visual acuity is lower by one or morelines,
`or if they develop worsening macular
`oedema, they needa furtherinjection of
`anti-VEGF.
`
`Trials of this dosing regime for AMD and
`diabetic macular oedema have shown
`that an averageof seveninjections are
`requiredin the first year of treatment and
`that outcomes are as goodasfor regular
`monthly injections. Thetrials used as their
`indication for re-treatment with anti-VEGF
`either a reductionin visual acuity or an
`increasein retinal thickness (measured
`using optical coherence tomography
`[OCT]); both were assessed at each visit.
`While visual acuity is easily measured,
`retinal thickness can only be measured
`accurately by OCT. These machines are
`costly and will only be available in major
`Continues overleaf >
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`Exhibit 2271
`
`Page 02 of 03
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`Exhibit 2271
`Page 02 of 03
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`

`DRUGS Continuec
`
`cities in low- and middle income countries.
`Wedon’t yet know howeffective PRN
`treatment might be whenretreatmentis
`guided byvisual acuity alone, as both
`visual acuity and retinal thickness were
`measured at eachvisit in thesetrials.
`Although intermittent regimes reduce
`the numberofinjections, patients still
`have to be reviewed every 1-2 months,
`whichleadsto very busyclinics; this is
`also a significant burdenfor the patients
`andfor their families.
`
`Which diseases can be
`treated?
`
`Age-related macular degeneration
`Lucentis, Avastin and Eyelea are equally
`effective in exudative AMD. There
`
`appearsto belittle difference between
`monthly and PRN dosing. The average
`(mean) improvementin vision is about
`1-2 lines, and about one-third of
`patients will improve by three or more
`lines. With a PRN regime, an average of
`seven injections will be required in the
`first year. Mostof these trials excluded
`eyes with a vision of less than 6/96
`(4/60), and treatmentis unlikely to be
`effective in advanced exudative AMD with
`sub-macularscarring or a vision of
`‘counting fingers’ or ‘hand movement’.
`Unfortunately, exudative AMD often
`co-exists with atrophic (‘dry’) AMD, and
`the anti-VEGF drugsonlytreat the
`exudative component. With longer
`follow-up (over 2 years), atrophic AMD
`may cause a gradual loss of vision
`despite effective anti-VEGF treatment.
`
`Diabetic macular oedema
`
`treating diabetic macular oedema, and
`the average improvementin vision is
`about 1.5 lines. Roughly 25% of patients
`will have theirvisual acuity improve by
`three or more lines and 50% bytwo or
`morelines. An average of seveninjections
`will be requiredin thefirst year of
`treatmentwith a PRN regime.
`Not all patients with diabetic macular
`oedema needto be treated with
`anti-VEGF. Laser treatmentstill has an
`important role: macular oedema which
`does notinvolvethe foveais best treated
`
`withlaser. These patients will normally
`have goodvision, andthelaserwill help to
`preserveit. Moreover, laseris usually
`effective with a single treatment, whichis
`much easierfor the patient than repeated
`monthly injections.
`If new vessels are present, they should
`be given pan-retinal laser treatmentfirst,
`before any macular oedemais treated
`using anti-VEGF. This is because
`anti-VEGF makes the new vessels regress
`very quickly. As the treated vessels
`becomefibrotic, they contract, which can
`cause a retinal detachment.
`
`Retinal vein occlusion
`There is good evidencefromclinicaltrials
`that all three anti-VEGF drugswill reduce
`theriskoflossofvision following central
`retinal vein occlusion. About 50% of
`
`patientswill gain three or more lines, with
`a mean improvementof abouttwolines.
`Thereis also a reduced risk of rubeosis
`and secondary glaucomawith anti-VEGF
`treatment.
`
`Lucentis has been shown to improve
`outcomesafter branchretinal vein
`
`Onceagain, there seemsto belittle
`difference between thedifferent
`anti-VEGF drugs.All three are effective at
`
`occlusion as well. However, as many of
`these patients will improve spontaneously,
`this evidenceis not quite as strong.
`
`In summary, anti-VEGF drugs are probably
`the mostsignificant advancein ophthal-
`mology in the last decade. They have
`enabledusto treat what were previously
`untreatable conditions. They are not a
`perfect solution, however.
`
`* They do not cure the underlying
`problem, so repeated treatmentis
`necessary and mostpatientswill require
`a lifetime of regular monitoring.
`The drugs are expensive, and even high-
`income countries have struggled with the
`costs andlogistics of deliveringthousands
`of intraocularinjections every year.
`¢ Although anti-VEGFdrugs are the most
`effective treatment for manyretinal
`diseases, the visual improvementis
`modest, averaging about twolines of
`vision. Relatively few patients will regain
`normalvision.
`* Patients who presentlate, with very
`advanced disease and a visualacuity of
`less than 3/60, may not benefit from
`treatment.
`
`* Most PRN treatment regimes rely on
`OCT imaging, whichisrarely available in
`low and middle income countries. We
`havelittle information on the use of
`anti-VEGF in this setting, and we cannot
`be sure that the good results achieved
`in Europe and North Americawill be
`replicated in Africa, India, or China.
`
`Despite these reservations, anti-VEGF
`drugs are goingto play an increasing role
`in the prevention of blindness worldwide.
`As the global population ages, and
`becomes more overweight, both AMD
`and diabetic retinopathy will become
`more common. The drugswill become
`cheaper, and we mayfind better ways of
`monitoring treatment so that expensive
`OCTis no longeressential.
`
`PUTSeMeeeeMea
`Clare Gilbert
`Co-director: Intemational Centre for
`Eye Health, Disability Group, London
`Schoolof Hygiene andTropical
`Medicine, London, UK.
`
`There are several reasons whyanti-VEGF
`agents are not recommended for acute,
`severe retinopathy of prematurity (ROP).
`
`* There has only been one randomised
`trial, which compared laser with
`Avastin (bevacizumab)for Type 1 ROP.
`It was only more effective in preventing
`early recurrenceof severe diseasein
`Zone 1 (posterior), but the recurrence
`rate in the laser arm wasworse than
`would be expected based on other
`studies. More babies died in the
`anti-VEGF arm of the trial, but the
`
`difference wasnotstatistically
`significant.
`* There are major concemsabout the
`short- and long-term impact of
`anti-VEGF agents on the lung, kidneys
`and brain of a baby.
`Follow-up studies, using fluorescein
`angiography, indicate that normal
`retinal vascularisation may not take
`place after administration of
`bevacizumab, with extensive areas of
`non-perfusion monthsafter treatment.
`* There are an increasing numberof
`case reports which showthat, although
`Avastin can lead to regression of ROP
`in the short term, the ROP can recur
`monthslater. This meansthat an acute
`disease with a knownnatural history
`has the potential to becomea chronic
`
`disease with an unknown and
`unpredictable natural history.
`* Some surgeonsuseAvastin for Stage
`4a or 4b ROPpriorto surgery. This can
`makethe surgery easier, but there is
`still the risk of systemic complications.
`The leaking capillaries presentin eyes
`with retinopathy increasetheriskof large
`molecules(e.g. anti-VEGFdrugs injected
`into the eye) entering the systemic circu-
`lation, and so the systemic safety of
`thesedrugs is important, particularly in
`preterm infants.If anti-VEGF drugs seem
`to be the only option to preserve sight
`whenextensive laserhasfailed, or the
`infantis too sickfor laser, this treatment
`can be offered, but only after parents
`have beenfully informed of the possible
`consequences.
`
`46 “®~\ COMMUNITY EYE HEALTH JOURNAL| VOLUME 27 ISSUE 87| 2014
`
`© The author/s and Community Eye Health Joumal 2014.This is an Open Access
`article distributed underthe Creative CommonsAttribution Non-Commercial License.
`
`Exhibit 2271
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`Page 03 of 03
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`Exhibit 2271
`Page 03 of 03
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