Tratamiento DMAE Húmeda

Diana González
Clínica de Retina
UNO
Intro
• Pérdida de visión central severa
• FR: edad, europeos, genético, fumar
• Comprobado que aspirina no se asocia
• Se recomienda vitaminas y suplementos de AREDS 2 solo para formas
intermedias y avanzadas
• Anti-VEGF como primera línea de tx
Dx Clínico
◆ Presencia de drusas de tamaño intermedio (>63 µm)
◆ Anormalidades en EPR
◆ Drusas reticulares, atrofia Geográfica, CNV, PVC
Clasificación AREDS
◆ No AMD (AREDS categoría 1): ninguna drusa o drusas pequeñas
◆ Temprana AMD (AREDS categoría 2): multiples pequeñas e
intermedias, o anomalias del EPR
◆ Intermedia AMD (AREDS categoría 3):
• Numerosas drusas intermedias
• Al menos una drusa grande (125 µm)
• Atrofia geográfica que no afecta fovea
Avanzada AMD (AREDS categoría 4)
◆ Atrofia geográfica que afecta fovea
◆ Maculopatía neovascular, DEP seroso o hemorrágico, o exudados
duros
◆ Cicatriz disciforme
Anti VEGF
• Aflibercept, pan–VEGF-A y bloqueante del PGF
• Similar en eficacia al ranibizumab en el VIEW trial
• 2-mg de aflibercept cada 4 semanas x 3 meses y después cada 8
semanas
• Se encontró similitud comparado con 0.5 mg ranibizumab cada 4
semanas
• Bevacizumab es un anticuerpo monoclonal que se une a todas las
isoformas de VEGF (off label)
• Ranibizumab es una IG recombinante humanizada isotipo G1 kappa
• Inhibe todas las isoformas biológicas de VEGF-A
• CATT es un trial multicentrico que comparó la seguridad de
bevacizumab vs ranibizumab con regimen PRN de uso mensual
• Al año, tuvieron equivalencia comparable de AV
• A los 5 años se observó que bevacizumab no mantenía la ganancia
visual, sin embargo el 50% presentaban AV de 20/40 o mejor
• Resultados similares se encontraron en el trial IVAN (2-year Inhibition
of VEGF in Age-related choroidal Neovascularization)
• Meta-analisis por Nguyen en 2018, 8,000 ojos
• Bevacizumab y ranibizumab = eficacia para BCVA
• Ranibizumab mayor reducción en CST macular
• Aflibercept y ranibizumab = BCVA y CST
• No se recomienda el uso combinado con esteroides
• DENALI y MONT BLANC (ranibizumab y verteporfin PDT comparado
con ranibizumab) no mostro significancia en combinarlos
• EVEREST demostró la necesidad de menos inyecciones de anti-VEGF
en variante PCV
NV Subfoveal
• PTD con veteporfin esta aprobado por la FDA para CNV clasica,
subfoveal
• Fotocoagulación (1990s) con pobres resultados
• Ya no se recomienda como tx
NV Yuxtafoveal
• Persistencia aún con tx
• Fuga dentro de las primeras 6 semanas
• Recurrencia, fuga fuera de las primeras 6 semanas
• 80% a los 5 años
• 52% progresaron a pérdida visual de 30 o más letras, comparado con
el grupo que no recibio tx, 61%
NV Extrafoveal
• Fotocoagulación redujo la tasa de pérdida visual severa los primeros 2
años
• Recurrencia o persistencia en el 50% a los 3 años
• 5 años despues, el 48% progresó a perdida visual de 30 o más letras
Indicaciones
• Conbercept y Abicipar aún no tienen aprobación por FDA
• HAWK y HARRIER mostraron que brolucizumab se equipara con
aflibercept en cuanto a BCVA, mientras que es mejor al disminuir más
CST
• Aprobado por la FDA en octubre 2019
• PRN con ranibizumab tienen una eficacia y seguridad comparable con
los regimen mensuales en un año de tx
• Precaución con bevacizumab, es menos efectivo
• Se recupera vision a los 2 años pero no se mantiene a los 5 aunque
50% la mantuvo 20/40 (CATT)
• “Treat and extend” como alternativa
• Lucentis Compared to Avastin Study (LUCAS) mostró similitude entre
el mensual y el T&E para bevacizumab y ranibizumab
Trials
• ANCHOR
• MARINA
• VIEW
• CATT
• IVAN
• HARBOR
Complicaciones
• Desgarros en el EPR
• Eventos tromboembólicos
• Incremento de PIO
• No se ha estudiado en embarazadas
• Endoftalmitis (≤1.0% al año en VIEW)
• No hubo eventos serios al año entre ranibizumab y aflibercept
• Bevacizumab
• Endoftalmitis por inyección (0.16%), DRT (0.16%), uveitis (0.09%), DRR
(0.02%), y HV (0.16%)
• Mayor rate de eventos sistémicos serios como thrombosis y
hemorragias GI comparado con el grupo de ranibizumab (24% vs.
19%; P=0.04) a los 2 años
• IVAN trial mostró mayor supresión de VEGF en suero
• Ranibizumab
• Endoftalmitis (≤1.0% a los 2 años, MARINA; menor 1 % en un año
ANCHOR
• DR o catarata (menor 0.1%)
• Pegaptanib
• Endoftalmitis (1.3%)
• Catarata (0.6%)
• DR (0.7%)
• Se reportaron eventos anafilácticos
https://www.aao.org/eye-health/tips-
prevention/promising-new-treatments-amd
• One promising approach that could be available soon is a refillable
drug reservoir. The port delivery system (PDS) is a tiny refillable device
that stores the anti-VEGF drug Lucentis. No bigger than a grain of rice,
the port is implanted into the wall of the eye, just under the eyelid,
during a surgical procedure. The device continuously releases drug to
the back of the eye over time. Instead of an injection every six to
eight weeks, patients might get a fill up once or twice a year at the
doctor’s office. The device can be refilled using a special needle. The
latest studies show many people treated this way were able to go 15
months in between treatments.
• Anti-VEGF treatments are effective because they target one key factor that contributes
to wet AMD: VEGF. But what if one drug could treat two underlying causes of AMD?
That’s the idea behind the drug faricimab. It targets both VEGF and the protein
angiopoietin-2. It’s injected into the eye like a standard anti-VEGF treatment, but it
lasts a long longer. The latest research shows patients could go up to four months in
between treatments. However, this data is so new that it has not yet been published in
a peer-reviewed journal.
• It may also be possible to combine two drugs and hit wet AMD with a double punch.
These combos could improve vision and make injections last longer. Cosopt
(dorzolamide-timolol), an eye drop already used to treat glaucoma, is being tested in
combination with anti-VEGF injections. Studies have shown that the duo can reduce
retinal fluid accumulation and last longer than an anti-VEGF injection alone. Opthea’s
OPT-302 targets a protein that contributes to wet AMD: angiopoietin II. Combining
Opthea with an anti-VEGF injection may work better and last longer than current anti-
VEGF injections.
• Faricimab is the first bispecific antibody designed specifically for the treatment of
retinal eye diseases that simultaneously binds to and inactivates Angiopoietin-2 (Ang-
2) and vascular endothelial growth factor A (VEGF-A). By targeting both Ang-2 and
VEGF-A, faricimab may lead to sustained efficacy at longer treatment intervals,
thereby improving vision outcomes for patients, according to a Genentech statement.
• The identically designed, multicenter, randomized, double-masked, active
comparator-controlled phase 3 TENAYA (NCT03823287) and LUCERNE (NCT03823300)
studies will evaluate the efficacy, safety, and durability of faricimab compared to
aflibercept for the treatment of wet AMD. In total, nearly 1,300 patients with wet AMD
will be randomized to receive either faricimab dosed at every 16 weeks (with an
option to drop to every 12 or 8 weeks), or aflibercept dosed every 8 weeks. The
primary endpoint of each study is the change in Best-Corrected Visual Acuity (BCVA) at
week 48 from baseline.
• OPT-302 is a soluble form of vascular endothelial growth factor
receptor 3 (VEGFR-3) or ‘Trap’ molecule that blocks the activity of
two proteins (VEGF-C and VEGF-D) that cause blood vessels to grow
and leak, processes which contribute to the pathophysiology of retinal
diseases. Opthea is developing OPT-302 for use in combination with
inhibitors of VEGF-A (e.g. Lucentis®/Eylea®). Combination therapy
of OPT-302 and a VEGF-A inhibitor achieves more complete
blockade of members of the VEGF family, blocking mechanisms
contributing to sub-optimal responses to selective VEGF-A inhibitors
and has the potential to improve vision outcomes by more completely
inhibiting the pathways involved in disease progression.
• Drugmakers are creating new anti-VEGF treatments that do not need to be
injected into the eye as often as Eyelea, Lucentis or Avastin.
• Novartis’ new drug, Beovu, is now approved for use in the United States. About
one in every three patients using Beovu can go for as long as three months
before needing another injection. Beovu may do a better job than other drugs
of drying retinal fluid in patients with wet AMD.
• Allergan’s Abicipar is still in phase 3 clinical trials and has not yet gained FDA
approval. Studies suggest this drug allows patients to go three months
between injections. This drug is also being evaluated for macular edema.
• Another injectable medicine — Sunitinib by Graybug Vision — has the potential
to give patients 6 months of durability between treatments. Sunitinab is just
entering Phase 2B clinical trials. It may still be 3 to 5 years away from
becoming available.
Beovu
• brolucizumab
• 6mg/0.05mL (single-dose vial or prefilled syringe)
• 6 mg (0.05 mL of 120 mg/mL solution) by intravitreal injection
monthly (~q25-31 days) x3 doses, THEN 6 mg q8-12weeks
• Human VEGF inhibitor; binds to the 3 major VEGF-A isoforms (eg,
VEGF110, VEGF121, VEGF165), thereby preventing interaction with
receptors VEGFR-1 and VEGFR-2
• By inhibiting VEGF-A, brolucizumab suppresses endothelial cell
proliferation, neovascularization, and vascular permeability
Abicipar
• ARPin molecules are derived from naturally occurring binding proteins that consist of repeat sequences
with capping structures at each end of the protein. DARPin molecules have three key properties that have
made them an important investigational class of binding protein for researchers: high binding affinity, low
molecular weight and customizable applications. These three properties make DARPin molecules
candidates for a broad range of therapeutic applications and are currently being investigated in
therapeutic categories such as ophthalmology, oncology and immuno-oncology. Allergan and Molecular
Partners are committed to advancing patient care through the development of molecules such as Abicipar.
• The BLA and MAA filings are based on data from two phase 3 trials, CEDAR and SEQUOIA, which supported
the noninferior efficacy of the Abicipar quarterly dosing regimen to maintain vision gains with more than
50 percent fewer injections versus ranibizumab (13 vs. 6) dosed monthly in the first year.
• The identical, global phase 3 head-to-head pivotal trials, CEDAR and SEQUOIA, assessed the efficacy and
safety of Abicipar compared with ranibizumab in treatment-naïve patients with neovascular AMD. The
primary endpoint measured the proportion of treated patients with stable vision at week 52 and, in both
studies, Abicipar demonstrated similar efficacy after 6 or 8 injections, compared to 13 ranibizumab
injections in the first year of this study. The overall adverse events were similar among the three treatment
arms (Abicipar dosed every 8 weeks, Abicipar dosed every 12 weeks, or ranibizumab dosed monthly).
 Sunitinib
• ALTISSIMO trial
1.The intravitreal sunitinib malate depot GB-102, 1 mg/1mg dosed every 6 months (n=21)
2.The intravitreal sunitinib malate depot GB-102, 2 mg/1mg dosed at baseline and 1 mg at month 6 (n=22)
3.Aflibercept 2 mg, dosed every 8 weeks (n=13)
• Fifty of 56 randomized patients completed the 12-month treatment phase. Following an interim safety analysis, the intravitreal
sunitinib malate depot GB-102, 2 mg, was discontinued.
• Dr. Khanani concluded that the median time to first supportive therapy with the intravitreal sunitinib malate depot GB-102 was 5
months. The intravitreal sunitinib malate depot GB-102, 1 mg, reduced annualized injection burden from 10 to four injections
per year (58% reduction) from the 12-month pre-enrollment period to the ALTISSIMO core trial period. Drug-related adverse
events with the intravitreal sunitinib malate depot GB-102, 1 mg, were mild to moderate. None led to drug discontinuation. No
serious adverse events, nor vision-threatening inflammation, were reported.
• Three patients exhibited transient particles in the anterior chamber that resolved without long-term consequence. Four patients
experienced transient intraocular inflammation that resolved with a short course of topical steroid. Mean change in best
corrected visual acuity trended lower with the intravitreal sunitinib malate depot GB-102, 1 mg, vs aflibercept. Of this trend,
observed in six patients, two patients suffered from adverse events unrelated to the intravitreal sunitinib malate depot GB-102.
Two suffered from uncontrolled disease despite frequent injections of anti – vascular endothelial growth factor blockade pre-
enrollment. Two patients experienced adverse events related to particle dispersion of the intravitreal sunitinib malate depot GB-
102. Anatomical control (central subfield thickness) was comparable between the intravitreal sunitinib malate depot GB-102
and aflibercept.
Veteporfina
• ◆ A severe decrease in central vision occurred within 1 week following
treatment in 1% to 4% of patients, and may be permanent182,252,253
• ◆ Infusion site extravasation
• ◆ Idiosyncratic back pain during infusion of the drug (1%–2% of
patients)182,252,253 P37 Age-Related Macular Degeneration PPP 37 ◆
Photosensitivity reaction (menor 3%) 3 The stated, current recommendations
are to avoid direct sunlight for the first 5 days after a treatment. Verteporfin is
contraindicated in patients with porphyria or a known allergy or sensitivity to
the drug. Careful consideration should be given to patients with liver
dysfunction and to patients who are pregnant, breastfeeding, or of pediatric
age, because these patients were not studied in published reports.
PFC
• Rupture of Bruch’s membrane with subretinal or vitreous hemorrhage
◆ Effects on the fovea in subfoveal or juxtafoveal CNV Thermal laser is
no longer recommended for subfoveal CNV. Introduction or
enlargement of a pre-existing scotoma, with or without VA loss, is not
a complication of thermal laser photocoagulation surgery; rather, it is
an anticipated side effect of the treatment. Similarly, recurrence or
persistence of CNV, or the development of new CNV and further
visual deterioration after adequate thermal laser surgery, is usually a
result of the disease process and is not a complication. These realities
must be emphasized to the patient and family before treatment.
Follow up
• The follow-up history should take into account the following: ◆
Symptoms, including decreased vision and metamorphopsia204 ◆
Changes in medications and nutritional supplements ◆ Changes in
medical and ocular history11,205,206 ◆ Changes in social history
(smoking)39-43
• In addition to the above recommendations, patients who have been treated with aflibercept, bevacizumab,
ranibizumab, or pegaptanib sodium injection; verteporfin PDT; or thermal laser photocoagulation surgery should
be examined at regular intervals by means of biomicroscopy of the fundus. Optical coherence tomography,209
OCTA, 271-274 fluorescein angiography,148,150,151 and fundus photography may be helpful to detect signs of
active exudation or disease progression and should be used when clinically indicated. In common clinical
practice, OCT is a simple, noninvasive procedure that is well accepted by the patient and provides important
information for the provider to manage AMD. Initial treatment and follow-up with intravitreal anti-VEGF therapy
(aflibercept, bevacizumab and ranibizumab) should be at approximately 4-week intervals.168,179,183 P39 Age-
Related Macular Degeneration PPP 39 Subsequent follow-up and treatment intervals vary depending on the
clinical findings and judgment of the treating ophthalmologist. After three loading doses administered at 4 week
intervals, a maintenance treatment regimen every 8 weeks with aflibercept has been shown to have comparable
efficacy to every 4 weeks of either ranibizumab and aflibercept in the first year of therapy.168 There is no
consensus about the ideal treatment intervals with antiVEGF agents. There are three protocols: monthly or
bimonthly injections, treat-and-extend, or PRN. A minority of retina specialists will treat patients monthly. Treat-
and-extend is based on anti-VEGF injection following an interval based on treatment response. Asneeded
treatment is based on the presence or absence of subretinal or intraretinal fluid. The few patients currently being
treated with pegaptanib sodium injection should have followup examinations approximately 6 weeks after each
injection.
• Subsequent examinations, OCT, OCTA, and fluorescein angiography
should be performed as indicated depending on the clinical findings
and the judgment of the treating ophthalmologist. Treated patients
should be instructed to report symptoms of endophthalmitis, retinal
detachment, or decreased vision, and they should be re-examined
promptly.
Fellow eye con nvc
• For patients with unilateral disease, the fellow eye without CNV remains at high
risk of developing advanced AMD.275 The risk can be lowered by as much as
36% over a 10-year period by taking the AREDS/AREDS2 supplements.5 Patients
should be instructed to monitor their vision and to return to the
ophthalmologist periodically, even in the absence of symptoms, but promptly
after the onset of any new or significant visual symptoms. Patients at
exceptionally high risk (e.g., the presence of advanced AMD in one eye and
large drusen with RPE changes in the fellow eye) may be examined more
frequently (i.e., every 6–12 months) in an effort to detect asymptomatic CNV at
a treatable stage. Since some patients with AMD also have cognitive
impairment, a family member or care assistant should prompt the patient to
self-test. Optical coherence tomography is useful and OCTA may be useful for
evaluating the status of high-risk fellow eyes.