Neovascular Age- Related Macular Degeneration: A Visual Acuity Model of Natural Disease Progression and Ranibizumab Treatment Effect

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1 Ctaton: CPT Pharmacometrcs Syst. Pharmacol. (2018) 7, ; do: /psp ARTICLE Neovascular Age- Related Macular Degeneraton: A Vsual Acuty Model of Natural Dsease Progreon and Ranbzumab Treatment Effect Zufar Mulyukov 1, *, Sebastan Weber 1, Etenne Pgeolet 1, Andreas Clemens 1,2, Thorsten Lehr 3, and Amy Racne 1 Intravtreal ranbzumab s a frst- lne therapy for neovascular age- related macular degeneraton (namd), but there s a need to optmze patent outcomes whle mnmzng treatment burden. Here, we developed an ndrect response, nonlnear, mxed effects model of dsease progreon and drug effect n ant- vascular endothelal growth factor (VEGF) treatment- naïve patents. A total of 1,524 treatment- naïve patents and 29,754 vsual acuty observatons from the ANCHOR, MARINA, PIER, and EXCITE clncal trals nformed the model. The model accurately descrbed natural namd dsease progreon and predcted mean vsual acuty gans n the HARBOR study, notably wth a 2.0 mg ranbzumab dose not used for model development. Furthermore, ndvdualzed treatment regmens were shown by smulaton to be a vable alternatve to the commonly used pro re nata or fxed monthly dosng regmen approaches. Therefore, ths model could be a useful tool to predct the outcomes of dfferent, more patent- talored treatment regmens n namd. CPT Pharmacometrcs Syst. Pharmacol. (2018) 7, ; do: /psp ; publshed onlne on 15 August Study Hghlghts WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Modelng can be used as a tool for nterpolatng and extrapolatng exstng knowledge to novel treatment regmens and doses. In namd, smulatons of treatment regmens have been used to supplement clncal data for ranbzumab, resultng n an update to the label for ndvdualzed treatment. WHAT QUESTION DID THIS STUDY ADDRESS? Ths study amed to develop a model that could accurately descrbe the longtudnal change n vsual acuty for natural dsease progreon n namd and enable smulatons of the ant-vegf treatment effect at dfferent dose regmens. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Ths study offers an externally evaluated model of natural namd dsease progreon and treatment effect of ranbzumab admnstered at therapeutc doses. HOW MIGHT THIS CHANGE DRUG DISCOVERY, DEVELOPMENT, AND/OR THERAPEUTICS? The devsed model could have utlty n predctng the result of clncal studes n namd and could be used as a supplementary tool n drug development by dentfyng effectve alternatve doses and treatment regmens of beneft to patents. Age- related macular degeneraton (AMD) s a degeneratve dsease affectng the macular regon of the retna, leadng to a progreve lo of vson. The most aggreve form s neovascular AMD (namd; also known as wet AMD), 1 whch s hstorcally responsble for ~80 90% of all AMD vson lo cases. 1,2 Overexpreon of vascular endothelal growth factor (VEGF) s a content feature of namd and nduces chorodal neovascularzaton (CNV), the formaton of abnormal blood veels that leak flud nto the subretnal space resultng n rapd vson lo. 1,3 6 Inhbton of VEGF causes neoveel regreon and reduces vascular permeablty, ultmately reducng the presence of pathologcal retnal flud. Consequently, ntraocular ant- VEGF therapy greatly mproves vsual acuty (VA) n patents wth namd. 7,8 Ranbzumab s a humanzed ant- VEGF monoclonal antbody fragment (Fab) that nhbts the bologcal actvty of multple soforms of VEGF- A. 9,10 It was frst approved for the treatment of namd n the Unted States n and n the European Unon n The pvotal MARINA 7 and ANCHOR 8 phase III studes, n whch patents receved fxed monthly ntravtreal njectons, ntally nformed the ranbzumab dosng regmen. Subsequent clncal experence suggested that le than monthly dosng may be feasble 1 Novarts Pharma AG, Basel, Swtzerland; 2 Faculty of Medcne, Cardology and Angology I, Heart Center Freburg Unversty, Freburg, Germany; 3 Clncal Pharmacy, Saarland Unversty, Saarbrücken, Germany. *Correspondence: Zufar Mulyukov (zufar.mulyukov@novarts.com) Receved 30 Aprl 2018; accepted 6 June 2018; publshed onlne on 15 August do: /psp

2 661 and offer advantages n treatment schedules to patents and overburdened healthcare systems. 13,14 Accordng to ts European label, ranbzumab s lcensed for admnstraton va ntravtreal njecton at a startng dose of 0.5 mg once monthly untl maxmum VA s acheved and/or there are no sgns of dsease actvty (typcally 3 or more monthly njectons; known as a loadng dose ). Thereafter, montorng and treatment regmens are ndvdualzed and talored by the physcan to the patent s need and dsease actvty. 12 Indvdualzed treatment regmens wth a fxed observaton vst schedule wth treatment gven as needed are referred to as pro re nata (PRN) regmens, 13 whereas n treat- andextend (T&E) regmens, 14 patents are treated at every vst, but the tme between vsts can be ncreased or decreased based on the physcan s aement of dsease actvty. In ths study, we am to predct patent treatment responses n whch patents are njected at fxed monthly, bmonthly, or quarterly ntervals agned by observaton of ndvdual treatment need after three monthly loadng njectons. In revewng the results, we expect to gan better understandng of ndvdualzed treatment regmens that optmze treatment by mnmzng treatment burden wthout compromsng effcacy. Modelng technques are partcularly attractve for such aements: once comprehensve evaluaton demonstrates a model can reproduce actual observed data, smulatons can allow relable nterpolaton or lmted extrapolaton of untested scenaros to support the development of alternatve ant- VEGF drugs or treatment regmens. Prevously, we developed a model for ranbzumab n patents wth namd utlzng 1- year data from the ANCHOR, 7 MARINA, 8 PIER 15, and EXCITE 16 clncal studes. Ths model supported treatment recommendatons for optmal dosng and a label update approved by the European Medcnes Agency (EMA). 17 Ths study wll further develop ths model to nclude second- year data from these trals. Ths study also ams to estmate effects of covarates, such as age, baselne VA, or gender, on treatment effcacy and vsual deteroraton rate n namd. External data from the HARBOR clncal tral 18 wll be used to evaluate the predctve performance of the model. METHODS Clncal studes Data from four multcenter, randomzed, double- blnded, phase III, ranbzumab clncal studes ANCHOR, 7 MARINA, 8 PIER 15, and EXCITE 16 were used to develop the model. All studes compled wth the Declaraton of Helsnk. The methodology of these trals has been extensvely descrbed elsewhere. 7,8,15,16 Brefly, male and female patents 50 years of age or greater and wth a study eye best- corrected vsual acuty (BCVA) score from Early Treatment Dabetc Retnopathy Study (ETDRS) letters were ncluded. All enrolled patents were treatment- naïve to ant- VEGF. The ANCHOR study compared the safety and effcacy of monthly ranbzumab (0.3 mg and 0.5 mg) to photodynamc therapy (PDT; verteporfn). 7 The MARINA study evaluated the effcacy of monthly dosng of ranbzumab 0.3 mg and 0.5 mg vs. sham, 8 whereas the PIER study determned the effcacy of ranbzumab 0.3 mg and 0.5 mg once- monthly for 3 months, then once- quarterly vs. sham. 15 The EXCITE study was an actve- controlled, three- arm study of ranbzumab 0.3 mg or 0.5 mg once- monthly for 3 months and then once- quarterly vs. ranbzumab 0.3 mg once- monthly (see Table 1). 16 The prmary end pont n all four studes was the mean change n BCVA score. The BCVA was aeed usng standardzed VA charts, expreed as the number of ETDRS letters rangng from The BCVA was aeed at baselne, 1 week after the frst njecton, and then monthly n all studes except the PIER study, n whch t was aeed quarterly at treatment vsts after the frst 3 months. All avalable ndvdual patent data from the EXCITE and MARINA studes were used for model buldng. The PDT treatment arm of the ANCHOR study was excluded from the dataset, as were second- year data from the PIER study, due to the nonrandomzed reagnment of patents to dfferent treatment arms. Thus, the ANCHOR and MARINA data span 2 years of treatment, whereas EXCITE and PIER data span 1 year of treatment. Model development Graphcal analy ndcated that the drug effect can best be descrbed usng an ndrect response pharmacoknetc (PK)/pharmacodynamc model. 19 An ndrect response model was, therefore, used to capture the gradual decrease of VA due to dsease progreon under sham treatment and the effect of vtreous ranbzumab on VA. The PK data were not systematcally collected, thus for all modelng we used results of a prevous populaton PK analy 20 that concluded the vtreous concentraton of ranbzumab follows frst- order elmnaton PKs, wth a half- lfe of 9 days and a coeffcent of varaton (CV) on nterndvdual varablty of about 22%. Due to the absence of vtreous PK data, ntersubject varablty of PK parameters was dsregarded. Mean BCVA score n the sham arm of the MARINA study gradually decreased over the 2- year study perod (Fgure 1). Vsual worsenng from natural dsease progreon can be descrbed usng an ndrect response model by treatng the BCVA score as not beng at steady state value k n /k out at baselne. Thus, the VA score n a typcal patent wll decrease from baselne value to the statonary value k n /k out at rate k out wth no treatment. Ths descrpton aumes delayed BCVA deteroraton at the same rate constant k out after dscontnuaton of treatment effect. Data from the EXCITE study support ths hypothe as the mean BCVA decreased n the ntertreatment ntervals n the q12w arms. Because most observed data correspond to monthly BCVA aements at trough drug concentratons, and there were no treatment nterruptons of suffcent duraton to remove the drug effect, some model parameters (e.g., half- maxmal effectve concentraton (EC 50 )) needed pror knowledge for convergence of model fttng. We used a Bayesan approach and defned nformatve pror dstrbutons around plausble values. We tested effects of age, baselne BCVA score, and gender covarates on vsual deteroraton rate parameter k out and maxmum drug effect parameters. The covarate effect coeffcents were gven weakly nformatve prors centered

3 662 Table 1 Summary of study data used for model development (ANCHOR, EXCITE, MARINA, and PIER studes) and external evaluaton (HARBOR) ANCHOR EXCITE MARINA PIER HARBOR Study duraton 2 years 1 year 2 years 2 years 1 year Actve- treatment controlled Sham- njecton controlled Sham- njecton controlled Monthly and as- needed (PRN) Study desgn Actve- treatment controlled (PDT, verteporfn) Mnmally clac or occult CNV CNV wth or wthout clac CNV All CNV leson types Clac, mnmally clac or occult CNV Incluson crtera Predomnantly clac CNV Treatment regmen q4w q4w q12w q12w q4w q4w q4w sham q12w q12w sham q4w q4w Treatment dose, mg No. of patents Injectons per patent Summary data Observatons per patent Summary data Percent male (8.3) 77.4 (7.6) 76.8 (7.6) 77.1 (6.6) 78.6 (6.2) 78.8 (7.9) 77.8 (7.1) 78.8 (8.4) 79.3 (8.3) 75.8 (7.0) 75.1 (7.5) Age (SD), years 77.3 (7.3) 75.9 (8.5) 53.1 (12.9) 53.7 (12.8) 53.9 (13.7) 55.8 (12.3) 53.7 (15.5) 55.1 (14.0) 54.2 (13.3) 53.5 (13.1) 56.5 (12.2) 57.7 (13.1) 55.8 (11.8) 47.1 (13.2) 47.1 (12.8) Baselne BCVA (SD), letters 10.1 (13.3) 9.2 (14.6) 1.1 (14.8) 0.3 (13.5) 15.1 (21.5) 7.2 (12.2) 7.1 (15.3) 10.9 (17.3) 4 (14.9) 3 (13.7) 7.9 (11.5) 9.4 (14.5) 12.6 (14.1) BCVA change at month 12 (SD), letters BCVA, best corrected vsual acuty; CNV, chorodal neovascularzaton; q4w/q12w, every 4/12 week admnstraton; PDT, photodynamc therapy; PRN, pro re nata. at zero and tested smultaneously. 21 In the fnal model, only those wth posteror means sgnfcantly dfferent from zero were retaned (.e., the posteror probablty was >95% for a coeffcent to be >0, or >95% to be <0). Data from ant- VEGF and sham treatment arms were modeled smultaneously. Model evaluaton and smulatons The fnal model was evaluated usng posteror vsual predctve checks (Fgure 2) and by smulatng mean BCVA change from baselne of monthly treatment arms from HARBOR (both 0.5 mg [n = 274] and 2.0 mg [n = 275] ranbzumab doses), a study not used for model development. 18 The study arms were smulated 500 tmes. Indvdual patent data from the HARBOR study were not avalable. Populaton parameters were sampled from posteror dstrbutons of model parameters, whereas covarates (age and baselne BCVA) were sampled from analyzed data, as mean BCVA and mean age were close to those n the HARBOR study. The predcted mean BCVA change from baselne (and 95% predcton nterval for the mean) was then compared to the observed HARBOR study results (Fgure 3). The dropout rate n the HARBOR study was about 6%, and small enough to be gnored. To llustrate the mpact of the patent s baselne BCVA and age on the vsual acuty mprovement, we smulated 1,000 studes of 1,000 patents each wth covarates sampled from analyzed data and presented the change from baselne BCVA at month 12 n Fgure 4a,b. The model was used to predct change from baselne BCVA score over 12 months at ndvdualzed treatment regmens. All patents were admnstered three ntal ntravtreal njectons at months 0, 1, and 2. If at month 3 the BCVA dd not mprove or decreased compared to the prevous vst at month 2, a patent was agned to monthly (q4w) treatment. Otherwse, the BCVA was observed at month 3 and agan f BCVA dd not mprove or decreased compared to the prevous vst at month 3, a patent was agned bmonthly treatment (q8w), or quarterly (q12w) otherwse. Ths resulted n ~40% at patents agned to q4w, 27% to q8w, and 33% to q12w dosng from a total of 300 patents n 1,000 smulated trals. Data analy Model fttng was performed usng Stan software verson (Stan Development Team, < Ordnary dfferental equatons were solved usng a dscrete approxmaton to reduce computatonal (see Stan model specfcaton n Supplementary Fle S1). RESULTS Data summary A total of 1,524 patents and 29,754 VA observatons nformed the model. The dataset from the four studes (MARINA, EXCITE, ANCHOR, and PIER) conted of BCVA score observatons at monthly (868 patents), quarterly (238 patents), and sham (298 patents) njectons. Mean baselne BCVA acro studes was 54 ± 13 letters (range, 3 84 letters). Mean age of patents at baselne was 77 ± 7.5 years (range, years), wth about 40% of patents beng male. CPT: Pharmacometrcs & Systems Pharmacology

4 663 Fgure 1 Mean best corrected vsual acuty (BCVA; Early Treatment Dabetc Retnopathy Study (ETDRS) letters) from the ranbzumab treatment arms of the ANCHOR, EXCITE, MARINA, and PIER studes (q4w, once monthly dosng; q12w, once quarterly dosng; sham, untreated arms). Incluson crtera for the ANCHOR and MARINA studes dffered by CNV type. As baselne BCVA score and CNV type are strongly correlated, baselne BCVA score rather than CNV type was tested as a covarate n the model. Model development Stmulaton of k n rather than suppreon of k out was selected to descrbe the drug effect as t led to better stablty of model ft wth no other sgnfcant dfferences. The structural ndrect response model of VA g (t) for the th patent s defned by: ) dg (t) C = k dt n, (1+E max (t) (t) k EC 50 +C(t) out, g (t) (1) g 0(t = 0) = g0 where C (t) s vtreous drug concentraton followng frstorder elmnaton PKs wth the same half- lfe of 9 days n all patents. It s estmated by settng the vtreous volume to 4 ml 22 for all patents, thus C (t) s dfferent between patents only due to dfferences n dosng. Parameters k n, and k out, are the BCVA score mprovement and deteroraton rate constants, respectvely, for the th patent, and EC 50 s the concentraton correspondng to half the maxmum effect. Wthout treatment, the BCVA score decreases from baselne value g 0 to a steady state g =k n, /k out,. Ant- VEGF treatment leads to a rapd ntal ncrease of VA, reachng a plateau after only a few njectons, reflectng the strong ntal VA response n treatment- naïve patents due to flud leakage resoluton where the room for mprovement n subsequent njectons decreases. To properly ft these data, we ntroduced tme dependence nto maxmum effect (E max ). The E max was set to start at a hgh ntal value and decrease to a lower steady state value by the end of the 3- month loadng dose perod. The tme- dependent E max (t) was parametrzed as follows: Here, the drug effect for th ndvdual starts from 0 E max +ΔE max E max (t) = E max +ΔE max 0 exp ( k Emax t ) and decreases to steady state value E max at the rate k Emax. Due to sparse (monthly) BCVA samplng, (2)

5 664 Fgure 2 Vsual predctve checks for ranbzumab treatment regmens. Charts show 10th, 50th, and 90th percentles for the observed best corrected vsual acuty (BCVA) change (Early Treatment Dabetc Retnopathy Study (ETDRS) letters) from baselne (sold lnes) n treatment arms of the analyzed studes and the medans (dotted lne) wth 95% confdence ntervals (shaded areas) of the same percentles from model- smulated data. CPT: Pharmacometrcs & Systems Pharmacology

6 665 Fgure 3 Comparson of the HARBOR study mean best corrected vsual acuty (BCVA; Early Treatment Dabetc Retnopathy Study (ETDRS) letters; black lne) and out of sample model predcted mean BCVA (ETDRS letters; dotted lne) for ranbzumab treatment regmens. Shaded area s 95% credble nterval for the predcted mean. k Emax parameter was not readly dentfable. Because hgh E max values are neceary only for the onset of treatment, the value of k Emax should correspond to a few weeks halflfe. Senstvty analy showed the model was not senstve to k Emax correspondng to half- lves between 1 and 3 weeks. Thus, we set k Emax = log (2)/14 days -1. Not all ndvdual random effects on model parameters were dentfable. Patents partcpated ether n sham or drug treatment arms, therefore, ndvdual random effects for untreated steady state BCVA score g defnes treated steady state BCVA, would be confounded. We used a random effect on E max parameters and modeled g = k n, /k out, wthout ndvdual random effects. Most patents were treated every month, therefore, vtreous drug concentratons were mantaned well above expected EC 50 values, whch mpeded estmaton of ndvdual EC 50 parameters, thus EC 50 was also estmated wthout ntersubject varablty. The remanng model parameters (baselne BCVA and E max, whch g 0, VA deteroraton rate constant k out,, drug effect parameters ΔE max and E 0 max ) ncluded ndvdual random effects. Because change from baselne VA at the study end was our end pont of nterest, unbased estmates of ntal or baselne BCVA values g 0 were crucal. 23 We modeled baselne VA g 0 as normally dstrbuted around observed value BVA : g 0 = BVA +η 1,. Effects of patent age, gender, and model- estmated baselne VA (g 0) on ΔE 0 max, E max and k out parameters were tested. Indvdual random effects and covarate effects on model parameter k out,,e max 0,ΔE max were n the followng form: ( ) ) βk,age AGE g 0 βk,bva θ k, = θ k ( β I(sex=male) k.sex e ηk, (3) where I s an ndcator functon, 77 s mean age (years), and 55 s mean BCVA (ETDRS letters) ( at baselne. Random ) effects η k, on four model parameters g 0,k out,e 0 max,δe max are aumed to be normally dstrbuted wth a covarance Σ. Observed BCVA values y,j of the th patent at tme t,j, were modeled as beng normally dstrbuted around predcted BCVA g(t,j ) wth resdual varance σ 2 :p(y,j θ,σ 2 ) N ( g ( ) t,j,θ ),σ 2, where θ denotes all ndvdual model parameters. We allowed for dfferent values of resdual varance for treatment and sham arms. Most patents were dosed monthly and full drug effect was mantaned. Only quarterly treatment arms dsplayed decrease of the effect at ntertreatment ntervals. Thus, the data manly nforms that EC 50 s le than the vtreous concentraton 1 month after an njecton (12.5 μg/ml) and comparable to or greater than the concentraton 3 months after an njecton (0.12 μg/ ml) two orders of magntude range. Thus, to deal wth dentfablty, the log- normal pror for EC 50 was centered at 2.5 μg/ ml and covered range of concentratons from 1 7 μg/ml wthn the SD. Smulatons of the ftted data were not senstve to the choce of the EC 50 pror, thus smulatons wth ntertreatment ntervals are relable, but only up to 12 weeks that was present n the ftted data. Weakly nformatve pror dstrbutons were agned to all other model parameters. Estmated parameters for the ndrect response model (Eq. 1) are presented n Table 2 and Table S1. Accordng to the ftted model, natural dsease progreon of a typcal patent wth namd leads to a gradual decrease of VA to a steady state value g 11 ETDRS letters, an upper lmt for defnton of near- blndne by the Internatonal Councl of Ophthalmology, 24 at the rate of about 20% per year for BCVA score above g. Very hgh varaton n ndvdual varablty n VA deteroraton rates k out was found (CV of 730%).

7 666 Fgure 4 (a) Best corrected vsual acuty (BCVA) score change from baselne after 12 months of 0.5 mg monthly ranbzumab treatment vs. patent s baselne BCVA score. (b) BCVA score change from baselne after 12 months of 0.5 mg monthly ranbzumab treatment vs. patent s age. ETDRS, Early Treatment Dabetc Retnopathy Study. Table 2 Model parameter estmates (means of the posteror parameter samples) Parameter Descrpton Estmate RSE, % k elm, 1/day Rate constant for drug elmnaton from the (t 1/2 = 9 days) 0, fxed vtreous g, letters Equlbrum BCVA reached at natural progreon 11 5 k out, 1/year BCVA deteroraton rate constant at natural 0.19 (t 1/2 = 3.6 years) 9 dsease progreon E max Drug effect on BCVA at mean age (77 years) ΔE max Addtonal drug effect at the onset of treatment k Emax, 1/day Rate of E max change (t 1/2 = 15 days) 0, fxed EC 50, μg/ml Drug concentraton for half of the maxmal effect β Emax,AGE Age effect on drug on E max IIV g 0, letters Interndvdual varablty IIV k out CV, % Interndvdual varablty IIV E max CV, % Interndvdual varablty IIV ΔE 0 max CV, % Interndvdual varablty 1,100 4 σ sham, letters Resdual error for BCVA of untreated patents 7 1 σ treatment, letters Resdual error for BCVA of treated patents BCVA, best corrected vsual acuty; CV, coeffcent of varaton; EC 50, half- maxmal effectve concentraton; E max, maxmum effect; t 1/2, half-lfe. The EC 50 estmate was 2 μg/ml (relatve standard error 30%), correspondng to a vtreous drug concentraton reached about 2.5 months after a sngle 0.5 mg njecton (Table 2). Among the tested covarate effects, only the effect of patent s age on steady state drug effect parameter E max was sgnfcant and ncluded n the fnal model. Model evaluaton and smulatons Goodne-of-ft plots (see Fgures S1-S5) dd not reveal model mpecfcatons. Vsual predctve checks show the model accurately descrbes the medan declne of VA n untreated patents and mprovement n a treated populaton, although the predcted nterndvdual varablty of the BCVA score change was slghtly larger n the model than n analyzed data (Fgure 2). Fgure 4 shows the mpact of baselne BCVA score and patent s age on BCVA change from baselne after 12- months treatment wth monthly 0.5 mg ranbzumab. There was a nearly lnear relatonshp between baselne BCVA and BCVA gan at study end (Fgure 4a). For every 10 letters of lower baselne BCVA, there are 3 letter gans n BCVA mprovement at the end of 12 months wth monthly treatment. CPT: Pharmacometrcs & Systems Pharmacology

8 667 Patent s age was a sgnfcant covarate on E max, wth older patents exhbtng a smaller mprovement n VA. However, the age effect s modest, wth a 4 ETDRS letter reducton n VA mprovement for 85 compared to 65 year- old patents (Fgure 4b). For comparson, the SD of the BCVA change from baselne to month 12 due to nterndvdual varablty s about 14 ETDRS letters. Predctve performance of the model was evaluated by comparng model predcted mean BCVA to observed mean BCVA from monthly treatment arms of the HARBOR study. The predcted mean BCVA change from baselne profles are n good agreement wth HARBOR, wth the 12- month end pont of 8.5 and 9.2 ETDRS letters mprovement n mean BCVA compared to observed 10 and 9 ETDRS letters for the 0.5 mg and 2.0 mg dose arms, respectvely. The smlarty between smulated responses for both doses suggests that, wth monthly dosng, a 0.5 mg dose s suffcent to mantan the treatment effect at maxmum levels (Fgure 3). Smulatons showed that the ndvdualzed treatment schedule based on observaton of ndvdual treatment Fgure 5 Smulaton results comparng q4w, q8w, and q12w, 0.5 mg ranbzumab treatment to an ndvdualzed regmen. Mean predcted change from baselne best corrected vsual acuty (BCVA; Early Treatment Dabetc Retnopathy Study (ETDRS) letters) presented as dotted lne, shaded area s 95% credble nterval for the predcted mean.

9 668 need could lead to a better clncal outcome compared wth a q12w regmen, wth an average mprovement of 6 vs. 4 ETDRS letters (Fgure 5). DISCUSSION Ths study succefully developed a model that accurately descrbes lo of VA durng natural namd progreon and the treatment effect of ntravtreal ranbzumab admnstered to patents wth namd at therapeutc doses. In contrast to prevous modelng approaches, 17,25 ths model descrbes natural dsease progreon, treatment effect, and rapd ntal vsual mprovement n a sngle model usng the largest number of analyzed studes. The model predcted mean BCVA outcomes n the HARBOR study, ncludng the 2.0 mg ranbzumab arm, a dose not used for model generaton. Modeled BVCA gan for HARBOR was ~9 ETDRS letters for both 0.5 mg and 2.0 mg doses, agreeng wth actual BCVA gans n the HARBOR study of 10.1 and 9.2 ETDRS letters for 0.5 and 2.0 mg doses, respectvely. 18 The MARINA study 8 has the largest amount of observatonal data and demonstrated a mean ETDRS letter mprovement of only seven letters at comparable values of the covarates. Ths may explan why the predcted mean letter responses for HARBOR n ths study s slghtly lower than the actual HARBOR values, but wthn a 95% credble nterval. The model accurately depcts medan change from baselne n both ant- VEGF and sham treated patents under monthly and quarterly treatment regmens. Hgh nterpatent varablty of BCVA score changes was well captured by the model through between- patent varablty of VA deteroraton rate constant and of the drug effect parameters. Sham treatment data n patents wth namd are no longer avalable as ant- VEGF treatment s now a standard of care, thus, the model provdes a unque opportunty to demonstrate BCVA score behavor under natural dsease progreon. The model descrbed a gradual decrease n BCVA to near blndne levels of 11 ETDRS letters n the absence of treatment. At ~3.5 years half- lfe for VA deteroraton, ths level would be reached beyond study duraton; however, varablty of the vsual deteroraton rate among patents was very hgh (700% CV), suggestng that patents requre mmedate treatment nterventon upon namd dagno. Snce publcaton of the pvotal clncal studes used for developng the model, patents are now treated earler n ther course of the dsease, whch mght nfluence the treatment effect on BCVA. However, by usng a Bayesan framework for the model, straghtforward updates are enabled usng data from newer studes. Furthermore, the model could provde a foundaton to be expanded to other ant- VEGF drugs, usng pror knowledge of natural dsease progreon and the modeled treatment effect of ranbzumab. Patent s age had a statstcally sgnfcant, but modest covarate effect on E max. A smaller treatment effect n older patents was expected due to decreased VA, even n the absence of CNV. Ths result agrees wth the recent AURA study, whch demonstrated the negatve effect of age at treatment ntaton on ant- VEGF treatment outcomes. 26 The EC 50 value of 2 μg/ml ndcates that at monthly dosng (wth C mn = 12.5 μg/ml) ntravtreal ranbzumab concentraton s contently hgher than EC 50, but the drug effect s suboptmal wth quarterly treatment (wth C mn = 0.12 μg/ml). Ths can be readly observed n the EXCITE study data by oscllatons n the q12w dosng arms (Fgure 1), where the mean VA decreases durng treatment ntervals. No oscllatons of mean BCVA are observed n q12w arms of the PIER study because BCVA was aeed only at treatment vsts. A prevously reported estmate of the analogous parameter IC 50 from a dfferent model examnng an E max -type effect of ntravtreal ranbzumab concentraton on BCVA was 6.5 μg/ml. 17 Ths broadly agrees wth our EC 50 value and s approxmately equal to vtreous drug concentraton 8 weeks after a sngle njecton of 0.5 mg of ranbzumab. Ranbzumab approval n namd was orgnally based on data for monthly dosng; however, other treatment regmens, such as PRN or T&E, wth smaller burden on the patent and healthcare systems, can be used for effectve dsease control. Our model was developed to have utlty n predctng patent outcomes usng prespecfed, ndvdualzed treatment regmes. A model based on VA alone has lmted applcablty to accurately predct response to regmens where re- treatment decsons are based on multple clncal factors. However, smulatons showed that the model can be appled to smulatons of ndvdualzed treatment regmens where there s no need to for multple retreatment decsons durng treatment as n T&E or PRN regmens. Smulatons usng our model demonstrated that ndvdualzed monthly, bmonthly, or quarterly treatment schedule based on observed re- treatment need could elct a better VA response compared wth a q12w regmen, wth a gan of 6 ETDRS letters. The mean number of njectons durng the frst year of treatment was 8.7, whereas a year of treatment after ntal loadng would requre 7.7 njectons per vst. The mean BCVA mprovement was worse than for monthly treatment (6 vs. 8.5 ETDRS letters) and smlar to BCVA mprovement at bmonthly treatment (Fgure 5), however, such ndvdualzed treatment greatly reduces the overall treatment burden compared to q4w wthout unneceary lo of vson n patents that need more frequent than q8w treatment. These results compare favorably wth PRN treatment data from the 1- year SUSTAIN study, where a mean BCVA gan of 3.8 letters and average 5.7 njectons per patent were reported wth a total of 12 vsts. 27 The smulaton results suggest that more proactve treatment regmes, such as T&E could be more benefcal than PRN, where treatment s admnstered only after dsease actvty s detected. Indeed, numerous studes have demonstrated the benefts of the T&E regmen compared wth PRN, resultng n ts approval by the regulatory authortes. The recent 12- month TREND study showed that ranbzumab 0.5 mg admnstered accordng to T&E regmen resulted n 6.2 ETDRS letters gan n BCVA at mean number of 8.7 njectons and vsts. 29 One lmtaton of the model s that t s based on data from studes of treatment- naïve patents, 7,8,15,16 thus, only treatment- naïve patent populatons can be smulated wth confdence usng ths model. Another lmtaton s that treatment ntervals longer than 12 weeks cannot be smulated due to dentfablty of a key model parameter EC 50. CPT: Pharmacometrcs & Systems Pharmacology

10 669 In concluson, VA modelng approaches have been succefully utlzed n the past to supplement clncal data decson makng and regulatory approvals. 17 It s envsaged that the model developed n ths study may have smlar future utlty n testng and supportng the development and approval of novel ant- VEGF treatment regmens and doses for namd therapy. Supportng Informaton Supplementary nformaton accompanes ths paper on the CPT: Pharmacometrcs & Systems Pharmacology webste. ( com) Fgure S1. Goodne-of-ft plots. Pars plot of ndvdual random effects. Fgure S2. Goodne-of-ft plots. Random effects vs. covarates. Fgure S3. Goodne-of-ft plots. Observatons vs. populaton predctons. Fgure S4. Goodne-of-ft plots.. Resduals vs. tme. Fgure S5. Goodne-of-ft plots.. Resduals vs. ndvdual predctons. Table S1. Correlatons of modeled random effects Fle S1. Stan model specfcaton fle Acknowledgment. The authors were asted n the preparaton of the manuscrpt by Karen Stanford, Novarts Ireland Lmted, Dubln, Ireland. Fundng. Zufar Mulyukov, Sebastan Weber, Etenne Pgeolet, Andreas Clemens, and Amy Racne are employed by Novarts Pharma AG. Wrtng support was funded by the study Novarts Pharma AG. Conflct of Interest. Sebastan Weber, Zufar Mulyukov, Etenne Pgeolet, Andreas Clemens, and Amy Racne are employees of Novarts Pharma AG and own stocks n the company. Thorsten Lehr has no conflct of nterest to declare. Author Contrbutons. Z.M., S.W., E.P., and A.R. wrote the manuscrpt. Z.M., S.W., E.P., A.R., A.C., and T.L. desgned the research. Z.M., S.W., and A.R. performed the research. 1. Ambat, J. & Fowler, B.J. Mechansms of age- related macular degeneraton. Neuron 75, (2012). 2. Wolf, A. & Kampk, A. Effcacy of treatment wth ranbzumab n patents wth wet age- related macular degeneraton n routne clncal care: data from the COMPASS health servces research. Graefes Arch. Cln. Exp. Ophthalmol. 252, (2014). 3. Augood, C.A. et al. 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Km, L.N., Mehta, H., Barthelmes, D., Nguyen, V. & Glles, M.C. Metaanaly of real- world outcomes of ntravtreal ranbzumab for the treatment of neovascular age- related macular degeneraton. Retna 36, (2016) The Authors CPT: Pharmacometrcs & Systems Pharmacology publshed by Wley Perodcals, Inc. on behalf of the Amercan Socety for Clncal Pharmacology and Therapeutcs. Ths s an open acce artcle under the terms of the Creatve Commons Attrbuton-NonCommercal Lcense, whch permts use, dstrbuton and reproducton n any medum, provded the orgnal work s properly cted and s not used for commercal purposes.