Wet age-re­lat­ed mac­u­lar de­gen­er­a­tion (AMD) is a chron­ic, pro­gres­sive reti­nal dis­ease and a lead­ing cause of se­vere vi­sion loss and blind­ness world­wide.¹ Al­though an­ti-VEGF ther­a­pies rev­o­lu­tion­ized care, the bur­den of treat­ment re­mains sub­stan­tial. Pa­tients of­ten re­quire fre­quent in­trav­it­re­al in­jec­tions, and, even with cur­rent 2^nd gen­er­a­tion an­ti-VEGF agents, many con­tin­ue to need treat­ment every one to three months to main­tain vi­sion.^2,3

In re­al-world prac­tice, the de­mands of fre­quent in­jec­tions and of­fice vis­its may con­tribute to dis­con­tin­u­a­tion and un­der­treat­ment. These gaps in treat­ment have been as­so­ci­at­ed with fluc­tu­a­tions in reti­nal flu­id, re­duced ad­her­ence, and poor long-term vi­su­al out­comes, un­der­scor­ing the need for more durable treat­ment ap­proach­es.^4-6 Stud­ies have shown that ap­prox­i­mate­ly 40% of pa­tients dis­con­tin­ue treat­ment with­in the first year de­spite ther­a­pies ca­pa­ble of pre­serv­ing vi­sion.⁷

To­day, the cen­tral chal­lenge in wet AMD is no longer ef­fi­ca­cy, but dura­bil­i­ty. For years, re­searchers have pur­sued ther­a­pies ca­pa­ble of sus­tain­ing dis­ease con­trol for sub­stan­tial­ly longer pe­ri­ods while pre­serv­ing vi­sion and re­duc­ing treat­ment bur­den.⁸

With sev­er­al next-gen­er­a­tion durable ther­a­pies now ad­vanc­ing through late-stage clin­i­cal de­vel­op­ment, reti­nal med­i­cine may be near­ing a piv­otal tran­si­tion that could re­de­fine how clin­i­cians think about treat­ment in­ter­vals, dis­ease con­trol, and long-term pa­tient out­comes.⁹

In ad­di­tion to pre­serv­ing vi­sion, an im­por­tant goal of reti­nal med­i­cine is re­duc­ing the treat­ment bur­den. Fre­quent in­jec­tions and of­fice vis­its cre­ate chal­lenges for pa­tients, care­givers, and physi­cian prac­tices, and con­tribute to the rate of treat­ment dis­con­tin­u­a­tion.^7,10,11 These fac­tors high­light why treat­ment bur­den has be­come an im­por­tant top­ic when as­sess­ing durable ther­a­pies.

For ex­am­ple, two ther­a­pies may re­port sim­i­lar re­duc­tions in treat­ment bur­den, yet one may re­quire sub­stan­tial­ly more load­ing dos­es or sup­ple­men­tal treat­ments than the oth­er. With­out un­der­stand­ing how the num­ber and tim­ing of res­cue or sup­ple­men­tal treat­ments were in­cor­po­rat­ed in­to the analy­sis, those dura­bil­i­ty pro­files may make it dif­fi­cult to com­pare the to­tal num­ber of in­jec­tions need­ed to main­tain or sus­tain dis­ease con­trol over a longer time hori­zon (see Ta­ble).¹²

The fol­low­ing ta­ble is an Oc­u­lar Ther­a­peu­tix post hoc analy­sis of pro­ject­ed treat­ment bur­den re­duc­tions in re­spec­tive stud­ies. Treat­ment bur­den cal­cu­la­tions use re­port­ed treat­ment counts in the in­ves­ti­ga­tion­al arms rel­a­tive to a pro­ject­ed on-la­bel afliber­cept (2 mg) dos­ing sched­ule. Ac­tu­al on-la­bel afliber­cept (2 mg) dos­ing sched­ules were used where avail­able for faricimab and afliber­cept (8 mg). For afliber­cept (8 mg), re­sults from the Q12 and Q16 arms were com­bined us­ing a sam­ple-size-weight­ed av­er­age. Load­ing dos­es were de­fined as reg­i­men-spe­cif­ic ad­min­is­tra­tions oc­cur­ring be­fore the main­te­nance phase and were in­clud­ed or ex­clud­ed as in­di­cat­ed. Re­sults are in­tend­ed to be il­lus­tra­tive as the analy­sis is sub­ject to the lim­i­ta­tions of cross-tri­al com­par­isons, such as dif­fer­ent en­roll­ment and res­cue cri­te­ria.¹³ The re­sults are not in­tend­ed to re­flect prod­uct ef­fec­tive­ness and may war­rant fur­ther study or analy­sis.

While treat­ment bur­den re­duc­tion is im­por­tant for most key stake­hold­ers, alone, his­tor­i­cal­ly it has not been rel­e­vant for U.S. Food and Drug Ad­min­is­tra­tion (FDA) ap­proval or la­bel­ing. Ac­cord­ing to agency guid­ance on the de­vel­op­ment of drugs for neo­vas­cu­lar AMD, “a de­crease in the num­ber of ad­min­is­tra­tions of avail­able ef­fec­tive ther­a­pies alone is not suf­fi­cient for the demon­stra­tion of ef­fi­ca­cy.”¹⁴

Treat­ment bur­den re­mains a key mea­sure of the pa­tien­t's ex­pe­ri­ence and an im­por­tant in­di­ca­tor of po­ten­tial re­al-world im­pact. But bur­den re­duc­tion can’t be viewed in iso­la­tion or at the ex­pense of a com­pre­hen­sive as­sess­ment and eval­u­a­tion. As new­er ther­a­pies emerge, re­duc­tions in treat­ment bur­den should be in­ter­pret­ed in the con­text of how they are cal­cu­lat­ed. A com­plete as­sess­ment of treat­ment bur­den con­sid­ers all pa­tient in­ter­ven­tions over time, not just those oc­cur­ring af­ter the load­ing phase.

If treat­ment bur­den tells us how many in­jec­tions a pa­tient had over time, res­cue-free rates an­swer a more di­rect ques­tion: how many pa­tients main­tained dis­ease con­trol (with­in pre­de­fined pa­ra­me­ters) on the as­signed treat­ment. For clin­i­cians plan­ning a year of care – and pa­tients plan­ning a year of vis­its – we be­lieve this may be one of the most mean­ing­ful mea­sures of dura­bil­i­ty.

In emerg­ing clin­i­cal tri­als for long-act­ing ther­a­pies in wet AMD, that dis­tinc­tion be­comes in­creas­ing­ly im­por­tant. A study may re­port an at­trac­tive treat­ment bur­den-re­duc­tion fig­ure while still re­quir­ing mul­ti­ple res­cue treat­ments. Con­verse­ly, a high res­cue-free rate sug­gests that a greater pro­por­tion of pa­tients main­tained dis­ease con­trol based on the treat­ment arm alone and with­out sup­ple­men­tal in­ter­ven­tion.¹⁵

For ex­am­ple, two pa­tients may achieve sim­i­lar vi­su­al acu­ity out­comes at a pri­ma­ry end­point time point, yet one may have re­quired mul­ti­ple sup­ple­men­tal treat­ments along the way while the oth­er re­mained res­cue-free.¹⁵ Look­ing on­ly at the fi­nal ef­fi­ca­cy re­sult may ob­scure how many pa­tients re­quired sup­ple­men­tal treat­ment – and when in the clin­i­cal tri­al they re­quired it – to achieve that out­come.¹⁵ There­fore, the fi­nal ef­fi­ca­cy re­sult would fail to cap­ture those im­por­tant dif­fer­ences in dura­bil­i­ty and over­all bur­den.

In clin­i­cal prac­tice, res­cue-free rates help pro­vide im­por­tant con­text for un­der­stand­ing how ef­fi­ca­cy out­comes are achieved and whether dis­ease con­trol was sus­tained with­out ad­di­tion­al in­ter­ven­tion. More­over, if a more durable treat­ment re­quires too many res­cues, the line be­tween monother­a­py and com­bi­na­tion ther­a­py gets blurred.

Dura­bil­i­ty is fun­da­men­tal­ly a time-based con­cept. A pa­tient who re­quires sup­ple­men­tal treat­ment short­ly af­ter re­ceiv­ing ther­a­py rep­re­sents a dif­fer­ent dura­bil­i­ty pro­file than a pa­tient who re­mains con­trolled for many months be­fore ad­di­tion­al in­ter­ven­tion be­comes nec­es­sary.

Time-to-first-res­cue analy­ses help pro­vide this per­spec­tive by il­lus­trat­ing not on­ly whether res­cue oc­curred, but when dis­ease con­trol was un­able to be main­tained.¹⁶ For ex­am­ple, a pa­tient re­quir­ing res­cue short­ly af­ter treat­ment may rep­re­sent a fun­da­men­tal­ly dif­fer­ent dura­bil­i­ty pro­file than a pa­tient who re­mains con­trolled for many months be­fore in­ter­ven­tion be­comes nec­es­sary, even if both are ul­ti­mate­ly cat­e­go­rized as hav­ing re­ceived sim­i­lar res­cue treat­ment.¹⁵

For clin­i­cians eval­u­at­ing sus­tained de­liv­ery ther­a­pies, tim­ing may be just as im­por­tant as fre­quen­cy when as­sess­ing true dura­bil­i­ty. Res­cue in­jec­tions close to the pri­ma­ry out­come may have a greater pos­i­tive im­pact on vi­su­al acu­ity than those that oc­cur ear­li­er. This fact is rec­og­nized by the FDA where tim­ing of res­cue in­jec­tions may di­rect­ly cor­re­late with vi­su­al out­comes in non-in­fe­ri­or­i­ty stud­ies.¹⁷

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