Retinal Physician - Revisiting an Early Treatment for Wet AMD
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`Revisiting an Early Treatment for Wet AMD
`
`Is there a role for thermal laser in the era of anti-VEGF therapy?
`
`September 1, 2011
`
`BBB bshare
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`Revisiting an Early Treatment for Wet AMD
`
`Is there a role for thermal laser in the era of anti-VEGF therapy?
`
`Jaclyn L. Kovach,MD= Ingrid U. Scott, MD, MPH
`
`Thermallaser photocoagulation of choroidal neovascularization associated with neovascular age-related macular
`degeneration (Figure 1) is a well-known technique that has been used since the 1970s and studied extensively in
`the decades that have followed. The successof the treatment, defined as a reduction of vision deterioration, is
`dependent on the location of the CNV and on the patientgs pretreatmentvision. The risks of laser-induced retinal
`damageand recurrent CNV,often culminating in severe vision loss consistent with the natural history of the
`condition, has led to the preferential use of antigvascular endothelial growth factor agents or photodynamic therapy
`for lesions underand nearthe fovea.In the current era of vision stabilization and potential improvementfollowing
`anti-VEGF therapy,is there a role for thermal laser photocoagulation in wet AMD?
`
`U.S. Pat. 9,254,338 Exhibit 2255
`
`Mylan v. Regeneron
`IPR2021-00881
`
`Exhibit 2255
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`Exhibit 2255
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`Retinal Physician - Revisiting an Early Treatment for Wet AMD
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`Figure 1. Laser therapy was a mainstay of treatment for CNV secondary to AMD,but anti-VEGF therapies
`have swiftly replaced laserasa first-line treatment strategy.
`
`EXTRAFOVEAL CNV
`
`In 1982, results from the Senile Macular Degeneration Study (SMDS) were published by the Macular
`Photocoagulation Study (MPS) group. This randomized, controlled clinical trial sponsored by the National Eye
`Institute investigated the efficacy of argon laser photocoagulation in preventing severe visual loss in eyes with
`symptomatic CNV outside the fovea secondary to AMD. Theeligibility criteria included CNV at a distance of 200-
`2500 ym from the center of the foveal avascular zone, best-corrected visual acuity of at least 20/100, and
`symptomsrelated to CNV (decreased acuity, distortion, monocular diplopia). Participants were assigned to either
`thermallaser treatment or observation.
`
`Argon thermallaser treatment was performed after a retrobulbar block using 200-m spots of 0.5-second duration
`to produce a white lesion that covered the entire neovascular complex (including adjacent blood, pigmentation or
`blocked fluorescence) and extended beyond the lesion by 100-125 ym onall sides. Patients were followed up at
`three and six monthsafter enrollment and at six-month intervals thereafter with as needed retreatment.
`
`Two hundredtwenty-four patients were enrolled, and 113 were treated with laser. One hundredfive patients were
`followed through one year and 20 through twoyears. After 18 months, 60% of untreated eyes, compared with 25%
`of treated eyes, hadlost six or morelines of vision. Complica tions included retrobulbar hemorrhagein three
`patients, new subretinal hemorrhage in 31 eyes post-treatment, and Bruchés membraneperforation in one eye.
`
`The SMDS demonstrated that thermal argon photocoagulation of symptomatic extra-foveal CNV reducestherisk of
`severevision loss. These results did not apply to patients with serous or hemorrhagic detachments of the RPE.'
`Five-year results from the SMDS showed that mean baseline BCVA wasapproximately 20/40 for eyes with
`extrafoveal CNV and had de creased to 20/125 in treated eyes and 20/200 in observed eyes, with a meanloss of
`5.2 and 7.1 Snellenlines, respectively.2 At the time, thermal laser photocoagulation wasthe first and only proven
`treatment for CNV caused by AMD.
`
`Busbeeet al. conducted a cost-utility analysis of thermal laser photocoagulation of extra-foveal CNV using the five-
`year data from the SMDSandreported that laser treatment resulted in a mean gain of 0.0740 qualityadjustedlife
`years (QALYs)perpatient treated, as compared to observation alone. The meancostof treatmentfor the average
`patient totaled $1,715. The cost per QALY ranged from $16,117 to $49,7663 for thermal laser and over $56,000for
`ranibizumab.‘ Asa potentially more cost-effective treatment option than ranibizumab, thermal laser
`photocoagulation of extrafoveal CNV secondary to AMDcould be anattractive managementalternative if the CNV
`is small, well defined, and distant from the fovea.
`
`JUXTAFOVEAL CNV
`
`In the 1990s, the MPS group evaluated the effectiveness of thermal laser photocoagulation for the treatment of
`juxtafoveal CNV,ie, well-defined lesions located within the foveal avascular zone but not extending through the
`Exhibit 2255
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`Exhibit 2255
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`Retinal Physician - Revisiting an Early Treatment for Wet AMD
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`geometrical center of the fovea. After five years, almost no eyes with juxtafoveal CNV treated with laser had an
`improvement in vision compared to baseline. Twenty-five percent of treated eyes and 15% of untreated eyes
`maintained their baseline visual acuity. More than twice as many treated patients compared to observed patients
`retained a visual acuity of 20/40 or better, and 25% of laser-treated eyes had a BCVA of 20/400 or worse,
`compared to 40% of untreated eyes. Mean BCVAat baseline for all patients was approximately 20/60, and afterfive
`years, mean BCVA was20/200 for treated eyes and 20/250 for observed eyeswith lossesof five and six lines,
`respectively.
`
`At five years, both groups hadlost vision, with severe vision loss occurring in 52% of laser-treated eyes and 61% of
`untreated eyes. The reasonfor poor long-term vision in the treated group was associated with the high frequency of
`persistent or recurrent CNV. Thirty-two percent of the treated group suffered persistent CNV, and 42% had
`recurrent CNV during the five years. This outcome translated to an estimated 78% five-year rate of persistent or
`recurrent CNVinvolving the center of the foveal avascular zone. Close followup was recommended, given the high
`rate of recurrent CNV.° Because both the thermallaser and untreated groups suffered a similar amountofvision
`loss, and treatment was associated with a high CNV recurrence rate, anti-VEGF therapy is generally favored for
`juxtafoveal CNV.
`
`SUBFOVEAL CNV
`
`The MPSalso evaluated the efficacy of thermal laser photocoagulation for subfoveal CNV. Theeligibility criteria
`included the presence of classic subfoveal CNV, welldemarcated boundaries, and a size of < 3.5 MPSdisc areas.
`Lesions were treated in their entirety with an outline of laser burns of 200-ym spot size and 0.5-second duration and
`were filled with overlapping laser burns to produceanintense, white laser lesion. Treatment extended 100 um
`beyond the peripheral boundariesof all lesion components except for blood, in which case only the blood was
`covered with laser.
`
`With regard to patients with new subfoveal CNV, mean BCVA was20/125 for treated and control eyes at baseline
`and decreased to 20/320 and 20/500 with a meanloss of 3.5 andfive lines, respectively, after four years. Forty-
`seven percent of untreated eyes and 22% of treated eyes lost six or more lines of visual acuity from baseline. Argon
`greenlaser and kryptonred laser were found to be equivalent. Patients in the treatment group often noticed an
`immediate loss of visual acuity following treatment.8
`
`The MPSalso evaluated patients who had received prior laser treatment for an extrafoveal or juxtafoveal
`neovascular lesion and subsequently presented with recurrent CNV through the geometrical center of the foveal
`avascular zone. These eyes were assigned randomly to laser treatment or observation. Laser treatment was
`performed with coverageofall classic and occult CNV components and 100 um beyondthe lesion. Treatment
`extended at least 300 pm into the previous treatment scar and included visible feeder vessels.
`
`At three years, the treated eyes had better visual acuity, but both groups hadlimited distance visual acuity. Baseline
`mean BCVAwas20/125for treated and control eyes, with decreases to 20/250 and 20/320 and losses of three and
`fourlines, respectively, after four years. At three years, 12% of treated eyes and 36% of untreated eyes hadlost six
`or morelines of BCVA from baseline.”
`
`Thermallaser photocoagulation can reduce the magnitude of vision loss secondary to subfoveal CNV associated
`with AMD. Anti-VEGF therapy has replaced this treatment modality for subfoveal lesions, given the potential for
`visual acuity recovery and stabilization with sustained anti-VEGF treatment. In patients with subretinalfibrosis,
`persistent leakage and poorvisual prognosis, photodynamic therapy may be performed more commonly than
`thermallaserin an effort to reduce the anti-VEGF treatment burden.
`
`OCCULT CNV
`
`Giventhe often indistinct borders of occult CNV and therisk of retinal pigment epithelial tears if a pigment epithelial
`detachment(PED)is present, thermal laser of occult subfoveal CNV has not been widely pursued. Several small,
`prospective studies have investigated the usefulness of indocyanine green angiography (ICGA), which offers
`improved CNV and feedervessel visualization, in guiding the treatment of extrafoveal or juxtafoveal CNV with
`thermal laser photocoagulation.
`
`Atleast half of the patients in these studies had a stabilization or improvement in vision. The percentage dropped to
`15% in patients with a PED.2"! ICGA-guided thermal photocoagulation of the hot spot of extrafovealretinal
`angiomatousproliferation lesions has been explored with limited short-term benefit.'2 With the treatment offibrotic
`
`Exhibit 2255
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`https://www.
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`Exhibit 2255
`Page 03 of 05
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`Retinal Physician - Revisiting an Early Treatment for Wet AMD
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`CNV using dynamic ICGA-guided focal thermal laser ablation of the perfusing afferent arteriole, subretinal fluid was
`eliminated, and small visual acuity improvements were achieved in 40% of patients studied.'? Anti-VEGF agents
`are widely accepted as thefirst-line treatment for occult CNV secondary to AMD.
`
`SUMMARY
`
`For the past 40 years, thermal laser photocoagulation has been a treatment option in the armamentarium of
`neovascular AMDtherapies. At the time ofits publication, the MPS offered evidence-based justification for the use
`of thermal laser as the only proven treatment for classic CNV secondary to AMD. Occult CNV lesions were
`excluded from these clinical trials, with no proven alternative treatments available. For classic CNV that met the
`eligibility criteria, thermal laser photocoagulation could, at best, provide a reductionin vision loss, but it carried
`significant risks.
`
`Even without large, prospective, randomized, controlled trials comparing anti-VEGF therapy to thermallaser, the
`improved visual potential offered by ranibizumab and bevacizumabhasled to a drastic reduction in the use of
`thermallaser therapy, with its significant risks of visual acuity loss and recurrent CNV. PDT is used more commonly
`than thermal laser and is sometimes administered in an attempt to decrease the frequency of intravitreal injections
`in patients with wet AMD.
`
`An argument can be madein favorof thermal laser photocoagulation for small, well-defined extrafoveal CNV, given
`its attractive cost and logistical burden profiles, but for the treatment of subfoveal and juxtafoveal CNV,either
`classic or occult, anti-VEGF therapy has been generally accepted as a more effective treatment option. RP
`
`REFERENCES
`
`1. Macular Photocoagulation Study Group. Argon laser photocoagulation for senile macular degeneration. Arch
`Ophthalmol. 1982;100:912-918.
`2. Macular Photocoagulation Study Group. Argon laser photocoagulation for neovascular maculopathy. Five-year
`results from randomizedclinical trials. Arch Ophthalmol. 1991;109:1109-1114.
`3. Busbee BG, Brown MM, Brown GC, Sharma S. CMEreview:A cost-utility analysis of laser photocoagulation for
`extrafoveal choroidal neovascularization. Retina. 2003;23:279-287.
`4. Hodge W, Brown A,CruessA,et al. Pharmacologic management of neovascular age-related macular
`degeneration: systematic review of economic evidence and primary economic evaluation. Can J Ophthalmol.
`2010;45:223-230.
`5. Macular Photocoagulation Study Group. Laser photocoagulation for juxtafoveal choroidal neovascularization:
`five-year results from randomized clinicaltrials. Arch Ophthalmol. 1994;112:500-509.
`6. Macular Photocoagulation Study Group. Laser photocoagulation of subfoveal neovascular lesions in age-related
`macular degeneration. Arch Ophthalmol. 1991;109:1220-1231.
`7. Macular Photocoagulation Study Group. Laser photocoagulation of subfoveal neovascularlesions in age-related
`macular degeneration:updatedfindings from two clinicaltrials. Arch Ophthalmol. 1993;111:1200-1209.
`8. Macular Photocoagulation Study Group. Visual outcome after laser photocoagulation for subfoveal choroidal
`neovascularization secondary to age-related macular degeneration:the influence of initial lesion size and initial
`visual acuity. Arch Ophthalmol. 1994;112:480-488.
`9. Weinberger AW, Knabben H,Solbach U, Wolf S. Indocyanine green guided laser photocoagulation in patients
`with occult choroidal neovascularisation. Br J Ophthalmol. 1999;83:168-172.
`10. Donati G, Kapetanios AD, Pournaras CJ. |CG-guided laser photocoagulation of juxtafoveal and extrafoveal
`occult choroidal neovascularization. Graefes Arch Clin Exp Ophthalmol. 1999;237:881-886.
`11. Da Pozzo S, Parodi MB, Ravalico G.A pilot study of |CG-guided laser photocoagulation for occult choroidal
`neovascularization presenting as a focal spot in age-related macular degeneration. /nt Ophthalmol. 2001;24:187-
`194.
`
`12. Gupta B, Jyothi S, Sivaprasad S. Current treatment options for retinal angiomatousproliferans (RAP). Br J
`Ophthalmol. 2010;94:672-677.
`13. Cousins SW, Bearelly S, Reinoso MA,et al. Dynamic indocyanine green angiography-guided focal thermallaser
`treatmentof fibrotic choroidal neovascularization. Graefes Arch Clin Exp Ophthalmol. 2008;246:1677-1683.
`
`Jaclyn L. Kovach, MD,is assistant professorof clinical ophthalmology at the Bascom PalmerEyeInstitute of the
`University of Miami Medical Center. Ingrid U. Scott, MD, MPH, is professor of ophthalmology and public health
`sciences at the Penn State Hershey Eye Center. Dr. Scott received minimal financial compensation as a
`consultant for Genentech. Dr. Kovach reports nofinancial interest in any products mentionedin this article. Dr.
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`Exhibit 2255
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`https://www.
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`Exhibit 2255
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`Retinal Physician - Revisiting an Early Treatment for Wet AMD
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`Scott can be reached via email at iscott@psu.edu.
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`Retinal Physician, |ssue: September 2011
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