AD­STI­LADRIN® (nad­o­fara­gene fi­rade­n­ovec-vncg) – A Grow­ing Body of Clin­i­cal Da­ta and Re­al-World Ev­i­dence

For more than three decades, Bacil­lus Cal­mette-Guérin (BCG) – an in­trav­es­i­cal im­munother­a­py orig­i­nal­ly de­vel­oped as a tu­ber­cu­lo­sis vac­cine and ap­proved by the U.S. Food and Drug Ad­min­is­tra­tion (FDA) in 1990 – has been the stan­dard of care for the treat­ment of non-mus­cle in­va­sive blad­der can­cer (NMIBC).^1-2 While an ef­fec­tive ini­tial ther­a­py, near­ly one-third of pa­tients treat­ed with BCG do not re­spond,¹ and among those who do re­spond, half will even­tu­al­ly ex­pe­ri­ence dis­ease re­cur­rence or pro­gres­sion.³ His­tor­i­cal­ly, these post-BCG pa­tients were left with dif­fi­cult choic­es, in­clud­ing los­ing their blad­der through rad­i­cal and in­va­sive surgery (called cys­tec­to­my) or risk­ing their can­cer re­cur­ring and pos­si­bly pro­gress­ing to more ad­vanced stages with poor­er prog­noses.

From an on­co­log­i­cal stand­point, rad­i­cal cys­tec­to­my is a cu­ra­tive treat­ment op­tion that can po­ten­tial­ly save the pa­tient’s life. From the pa­tient’s per­spec­tive, how­ev­er, this has long been thought a last re­sort treat­ment be­cause it is in­va­sive, ir­re­versible, and car­ries sig­nif­i­cant risks and long-term com­pli­ca­tions that im­pact qual­i­ty of life. Ac­cord­ing to our mar­ket re­search at Fer­ring Phar­ma­ceu­ti­cals, pre­serv­ing the blad­der with­out risk­ing can­cer pro­gres­sion is a pri­ma­ry treat­ment goal for near­ly 95% of health­care providers treat­ing NMIBC pa­tients. How­ev­er, pa­tients who choose to keep their blad­ders, risk their can­cer re­cur­ring, re­quir­ing re­peat­ed sur­gi­cal re­sec­tions; and in a pro­por­tion of pa­tients, pro­gress­ing to mus­cle-in­va­sive or metasta­t­ic stage that can be dead­ly. For too long, their op­tions re­mained stag­nant.

Af­ter decades of lit­tle progress, the ap­proval of AD­STI­LADRIN^® (nad­o­fara­gene fi­rade­n­ovec) trans­formed this par­a­digm for BCG-un­re­spon­sive NMIBC with car­ci­no­ma in situ (CIS) with or with­out pap­il­lary tu­mors (±Ta/T1).⁴ As the first and on­ly in­trav­es­i­cal non-repli­cat­ing gene ther­a­py for BCG-un­re­spon­sive NMIBC, it of­fers pa­tients a blad­der-spar­ing op­tion which is tol­er­a­ble and ef­fec­tive. AD­STI­LADRIN is de­liv­ered di­rect­ly in­to the blad­der for one hour through an out­pa­tient pro­ce­dure, with a con­ve­nient dos­ing sched­ule of once every 3 months. Chang­ing the tra­jec­to­ry for cer­tain pa­tients by bring­ing this much-need­ed in­no­va­tion to the mar­ket, ad­dress­ing a crit­i­cal un­met need, is an in­spir­ing 30-year jour­ney marked by pas­sion­ate per­sis­tence, ground­break­ing dis­cov­er­ies, ma­jor in­vest­ments, and a firm be­lief in the po­ten­tial of in­ter­fer­on and gene ther­a­py. This la­bo­ri­ous and Her­culean ef­fort – much of it led by Col­in Din­ney, MD, of The Uni­ver­si­ty of Texas MD An­der­son Can­cer Cen­ter – re­quired over­com­ing two sig­nif­i­cant hur­dles, one tech­ni­cal and the oth­er reg­u­la­to­ry.

The im­me­di­ate hur­dle was the blad­der it­self. NMIBC is a lo­cal dis­ease that ide­al­ly is ad­dressed with lo­cal­ized treat­ment. For years, the med­ical com­mu­ni­ty rec­og­nized the an­ti­tu­mor ef­fects of in­ter­fer­on. Ear­ly stud­ies sug­gest­ed that in­still­ing in­ter­fer­on in­to the blad­der pro­duces some ev­i­dence of pre­vent­ing re­cur­rence, though the ef­fect was lim­it­ed. The chal­lenge was that the nat­ur­al void­ing func­tion of the blad­der did not al­low for re­ten­tion of in­ter­fer­on in­side the blad­der long enough to sus­tain a ther­a­peu­tic con­cen­tra­tion, lim­it­ing its ef­fi­ca­cy.

AD­STI­LADRIN helped reimag­ine drug de­liv­ery to the blad­der. Us­ing a non-repli­cat­ing ade­n­ovirus vec­tor con­tain­ing the gene for in­ter­fer­on al­fa-2b, AD­STI­LADRIN de­liv­ers the ac­tive in­ter­fer­on gene in­to the cells of the blad­der wall, caus­ing the cells to se­crete high and tran­sient lo­cal lev­els of in­ter­fer­on al­fa-2b pro­tein. While AD­STI­LADRIN is on­ly ex­posed to the blad­der for one hour af­ter in­stil­la­tion, the vi­ral-vec­tor is tak­en up by blad­der cells, es­sen­tial­ly turn­ing them in­to in­ter­fer­on mi­cro­fac­to­ries,⁴ and in­creas­ing the time the blad­der is ex­posed to in­ter­fer­on. Con­tin­u­ous ex­po­sure to ther­a­peu­tic lev­els of in­ter­fer­on elic­its its well-known di­rect and in­di­rect an­ti-tu­mor ef­fects and en­hances the body’s own nat­ur­al de­fens­es against can­cer (known as im­munother­a­py).

Over­com­ing the tech­ni­cal hur­dle rep­re­sent­ed an in­cred­i­ble mile­stone, but there was still a reg­u­la­to­ry chal­lenge. At the time, there were many de­f­i­n­i­tions of pa­tients who no longer re­spond to BCG – BCG re­lapse, BCG re­frac­to­ry, BCG in­tol­er­ant – but no stan­dard­ized de­f­i­n­i­tion that could be used as in­clu­sion cri­te­ria for clin­i­cal tri­als. Work­ing col­lab­o­ra­tive­ly, the uro-on­col­o­gy med­ical com­mu­ni­ty and the U.S. Food and Drug Ad­min­is­tra­tion (FDA) es­tab­lished the de­f­i­n­i­tion and pa­tient cri­te­ria for “BCG-un­re­spon­sive” NMIBC in 2018.⁵ The FDA’s guid­ance for the in­dus­try pro­vid­ed spe­cif­ic rec­om­men­da­tions for clin­i­cal tri­al de­signs and end­points for new treat­ments, which played a piv­otal role in shap­ing the clin­i­cal and reg­u­la­to­ry frame­work and ul­ti­mate­ly, sup­port­ing the de­vel­op­ment of AD­STI­LADRIN and the even­tu­al FDA ap­proval on De­cem­ber 16, 2022, in adult pa­tients with high-risk BCG-un­re­spon­sive NMIBC with CIS with or with­out pap­il­lary tu­mors (±Ta/T1). When the Phase 3 re­sults were pub­lished, a Lancet On­col­o­gy ed­i­to­r­i­al even asked the ques­tion, could AD­STI­LADRIN be “a new gold stan­dard for BCG-un­re­spon­sive blad­der can­cer?”⁶

To­day, AD­STI­LADRIN is rec­og­nized as a ground­break­ing blad­der-spar­ing treat­ment op­tion for BCG-un­re­spon­sive NMIBC pa­tients and is a rec­om­mend­ed treat­ment op­tion by the In­ter­na­tion­al Blad­der Can­cer Group (IBCG),⁷ the NC­CN Clin­i­cal Prac­tice Guide­lines in On­col­o­gy (NC­CN Guide­lines) and the AUA/SUO guide­lines.^8-9 This is based on the strength of its clin­i­cal ev­i­dence from the piv­otal Phase 3 tri­al con­duct­ed by the So­ci­ety of Uro­log­ic On­col­o­gy Clin­i­cal Tri­als Con­sor­tium (SUO-CTC), in which 51% (50/98) of pa­tients with CIS +/- high-grade Ta/T1 were dis­ease free by 3 months (de­fined as a com­plete re­sponse or CR) af­ter a sin­gle in­stil­la­tion of AD­STI­LADRIN. Of the pa­tients (n=50) who achieved a com­plete re­sponse, 46% re­mained free of high-grade re­cur­rence at 12 months. The most com­mon ad­verse events (AEs) ob­served in the study were: in­stil­la­tion site dis­charge (33%), fa­tigue (24%), blad­der spasm (20%), mic­turi­tion ur­gency (19%), and hema­turia (17%). These AEs were mild to mod­er­ate in in­ten­si­ty gen­er­al­ly re­solv­ing in a cou­ple of days and less than 2% of pa­tients dis­con­tin­ued treat­ment due to AEs.

AD­STI­LADRIN was ful­ly launched in the Unit­ed States in Jan­u­ary 2024. Re­cent­ly, Mayo Clin­ic con­duct­ed an in­de­pen­dent ret­ro­spec­tive as­sess­ment (n=46) of pa­tients com­mer­cial­ly treat­ed with AD­STI­LADRIN, pro­vid­ing the first re­al-world ev­i­dence of its ef­fec­tive­ness and tol­er­a­bil­i­ty, adding to the body of ev­i­dence for treat­ing BCG-un­re­spon­sive NMIBC pa­tients. Among 24 evalu­able pa­tients with BCG-un­re­spon­sive CIS +/- high-grade Ta/T1, 79% (19/24) had a com­plete re­sponse at 3 months, with 84% (16/19) main­tain­ing this re­sponse at a me­di­an fol­low-up of 7.3 months. AEs were con­sis­tent with Phase 3 ob­ser­va­tions.¹⁰ These da­ta were not fund­ed or sup­port­ed by Fer­ring Phar­ma­ceu­ti­cals.

More re­cent­ly, Fer­ring an­nounced re­sults from an on­go­ing Phase 3b tri­al of AD­STI­LADRIN in BCG-un­re­spon­sive CIS ± high-grade Ta/T1 pa­tients (n=20) in Japan. At 3 months, 75% (15/20) of pa­tients achieved a com­plete re­sponse.¹¹ Over­all, 80% of par­tic­i­pants ex­pe­ri­enced a drug–re­lat­ed AE, all of which were ei­ther Grade 1 (84.2%) or Grade 2 (15.8%).

The piv­otal Phase 3 re­sults for AD­STI­LADRIN from SUO-CTC, the in­de­pen­dent re­al-world re­sults from Mayo Clin­ic, and our in­ter­im Japan­ese Phase 3b re­sults, all con­tin­ue to build a con­sis­tent body of ev­i­dence for ef­fi­ca­cy, safe­ty and tol­er­a­bil­i­ty of AD­STI­LADRIN. To date, there have been no se­vere AEs (Grade 4 or 5) re­port­ed in clin­i­cal tri­als.

With AD­STI­LADRIN, Fer­ring is re­defin­ing the fu­ture of NMIBC. Pa­tients who do not re­spond to BCG now have an­oth­er op­tion – a well-tol­er­at­ed, ef­fec­tive, con­ve­nient (dosed once every 3 months), lo­cal­ized treat­ment that pro­vides durable blad­der preser­va­tion with rare risk of mus­cle-in­va­sive dis­ease pro­gres­sion.

Fer­ring has a stead­fast ded­i­ca­tion to sci­ence and an un­wa­ver­ing com­mit­ment to the blad­der can­cer com­mu­ni­ty. There­fore, our work has not stopped with the ap­proval and launch of AD­STI­LADRIN. We con­tin­ue to ex­plore the full po­ten­tial of AD­STI­LADRIN in blad­der can­cer with sev­er­al on­go­ing clin­i­cal tri­als. We are hope­ful that these ad­di­tion­al stud­ies will fur­ther build on the grow­ing body of ev­i­dence that, we be­lieve, would con­tin­ue to sup­port the emerg­ing role of AD­STI­LADRIN as the new stan­dard of care and the back­bone ther­a­py for NMIBC pa­tients.

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IN­DI­CA­TION

AD­STI­LADRIN is a non-repli­cat­ing ade­n­ovi­ral vec­tor-based gene ther­a­py in­di­cat­ed for the treat­ment of adult pa­tients with high-risk Bacil­lus Cal­mette-Guérin (BCG)-un­re­spon­sive non-mus­cle in­va­sive blad­der can­cer (NMIBC) with car­ci­no­ma in situ (CIS) with or with­out pap­il­lary tu­mors.

IM­POR­TANT SAFE­TY IN­FOR­MA­TION

CON­TRAINDI­CA­TIONS:AD­STI­LADRIN is con­traindi­cat­ed in pa­tients with pri­or hy­per­sen­si­tiv­i­ty re­ac­tions to in­ter­fer­on al­fa or to any com­po­nent of the prod­uct.

WARN­INGS AND PRE­CAU­TIONS:

• Risk with de­layed cys­tec­to­my: De­lay­ing cys­tec­to­my in pa­tients with BCG-un­re­spon­sive CIS could lead to de­vel­op­ment of mus­cle in­va­sive or metasta­t­ic blad­der can­cer, which can be lethal. If pa­tients with CIS do not have a com­plete re­sponse to treat­ment af­ter 3 months or if CIS re­curs, con­sid­er cys­tec­to­my.
• Risk of dis­sem­i­nat­ed ade­n­ovirus in­fec­tion: Per­sons who are im­muno­com­pro­mised or im­mun­od­e­fi­cient may be at risk for dis­sem­i­nat­ed in­fec­tion from AD­STI­LADRIN due to low lev­els of repli­ca­tion-com­pe­tent ade­n­ovirus. Avoid AD­STI­LADRIN ex­po­sure to im­muno­com­pro­mised or im­mun­od­e­fi­cient in­di­vid­u­als.

DOSAGE AND AD­MIN­IS­TRA­TION: Ad­min­is­ter AD­STI­LADRIN by in­trav­es­i­cal in­stil­la­tion on­ly. AD­STI­LADRIN is not for in­tra­venous use, top­i­cal use, or oral ad­min­is­tra­tion.

USE IN SPE­CIF­IC POP­U­LA­TIONS: Ad­vise fe­males of re­pro­duc­tive po­ten­tial to use ef­fec­tive con­tra­cep­tion dur­ing AD­STI­LADRIN treat­ment and for 6 months af­ter the last dose. Ad­vise male pa­tients with fe­male part­ners of re­pro­duc­tive po­ten­tial to use ef­fec­tive con­tra­cep­tion dur­ing AD­STI­LADRIN treat­ment and for 3 months af­ter the last dose.

AD­VERSE RE­AC­TIONS: The most com­mon (>10%) ad­verse re­ac­tions, in­clud­ing lab­o­ra­to­ry ab­nor­mal­i­ties (>15%), were glu­cose in­creased, in­stil­la­tion site dis­charge, triglyc­erides in­creased, fa­tigue, blad­der spasm, mic­turi­tion (uri­na­tion ur­gency), cre­a­ti­nine in­creased, hema­turia (blood in urine), phos­phate de­creased, chills, pyrex­ia (fever), and dy­suria (painful uri­na­tion).

You are en­cour­aged to re­port neg­a­tive side ef­fects of pre­scrip­tion drugs to FDA.

Vis­it www.FDA.gov/med­watch or call 1-800-332-1088. You may al­so con­tact Fer­ring Phar­ma­ceu­ti­cals at 1-888-FER­RING.

Please see full Pre­scrib­ing In­for­ma­tion for AD­STI­LADRIN.

Ref­er­ences

¹ Boor­jian SA, Ale­mozaf­far M, Kone­ty BR, et al. In­trav­es­i­cal nad­o­fara­gene fi­rade­n­ovec gene ther­a­py for BCG-un­re­spon­sive non-mus­cle-in­va­sive blad­der can­cer: a sin­gle-arm, open-la­bel, re­peat-dose clin­i­cal tri­al. Lancet On­col 2021; Ac­cessed Apr. 2025.

² A.C. An­tonel­li, A. Binyamin, T.M. Hohl, et al. Bac­te­r­i­al im­munother­a­py for can­cer in­duces CD4-de­pen­dent tu­mor-spe­cif­ic im­mu­ni­ty through tu­mor-in­trin­sic in­ter­fer­on-γ sig­nal­ing, Proc. Natl. Acad. Sci. U.S.A. 117 (31) 18627-18637; Ac­cessed Apr. 2025.

³ Ka­mat AM, Lern­er SP, O’Don­nell M, et al. Ev­i­dence-based as­sess­ment of cur­rent and emerg­ing blad­der- spar­ing ther­a­pies for non–mus­cle-in­va­sive blad­der can­cer af­ter Bacil­lus Cal­mette-Guerin Ther­a­py: a sys­tem­at­ic re­view and meta-analy­sis. Eur Urol Onc. 2020;3(3):318-340. doi:10.1016/j.euo.2020.02.006; Ac­cessed Apr. 2025.

⁴ AD­STI­LADRIN. Pre­scrib­ing In­for­ma­tion. Fer­ring Phar­ma­ceu­ti­cals. 2024. https://fer­ringusa.com/wp-con­tent/up­loads/sites/12/2024/10/Ad­sti­ladrin_PI.pdf. Ac­cessed Apr. 2025.

⁵ BCG-Un­re­spon­sive Non­mus­cle In­va­sive Blad­der Can­cer: De­vel­op­ing Drugs and Bi­o­log­ics for Treat­ment – Dig­i­tal Col­lec­tions – Na­tion­al Li­brary of Med­i­cine.” Nih.gov, 2018, col­lec­tions.nlm.nih.gov/cat­a­log/nlm:nl­muid-101733968-pdf. Ac­cessed Apr. 2025.

⁶ Kulka­rni, G. S. (2021). Nad­o­fara­gene fi­rade­n­ovec: a new gold stan­dard for BCG-un­re­spon­sive blad­der can­cer? The Lancet On­col­o­gy, 22(1), 8–9. https://doi.org/10.1016/s1470-2045(20)30586-6. Ac­cessed Apr. 2025.

⁷ Li R, Hens­ley PJ, Gup­ta S, et al. Blad­der-spar­ing Ther­a­py for Bacil­lus Cal­mette-Guérin-un­re­spon­sive Non-mus­cle-in­va­sive Blad­der Can­cer: In­ter­na­tion­al Blad­der Can­cer Group Rec­om­men­da­tions for Op­ti­mal Se­quenc­ing and Pa­tient Se­lec­tion. Eur Urol. 2024;86(6):516-527. doi:10.1016/j.eu­ruro.2024.08.001. Ac­cessed Apr. 2025.

⁸ Na­tion­al Com­pre­hen­sive Can­cer Net­work. Blad­der Can­cer (Ver­sion 1.2025). Avail­able at: https://www.nc­cn.org/pro­fes­sion­als/physi­cian_gls/pdf/blad­der.pdf. Ac­cessed Apr. 2025.

⁹ Cole­man JA, Clark PE, Bixler BR, et al. Di­ag­no­sis and Man­age­ment of Non-metasta­t­ic Up­per Tract Urothe­lial Car­ci­no­ma: AUA/SUO Guide­line. J Urol. 2023;209(6):1071-1081. Ac­cessed Apr. 2025.

¹⁰ Moy­er J, Du­rant A, Nguyen M. Re­al-world out­comes of nad­o­fara­gene fi­rade­n­ovec in BCG-un­re­spon­sive non-mus­cle in­va­sive blad­der can­cer. Pre­sent­ed at the An­nu­al Meet­ing of the Amer­i­can So­ci­ety of Clin­i­cal On­col­o­gy GU, Feb­ru­ary 2025.

¹¹ In­oue K, Kikuchi E, Nishiya­ma H, Na­su Y, et al. Ef­fi­ca­cy and Safe­ty of Nad­o­fara­gene Fi­rade­n­ovec for BCG-Un­re­spon­sive Non–Mus­cle-In­va­sive Blad­der Can­cer: Ini­tial Re­sults From an On­go­ing Japan­ese Phase 3 Tri­al. Pre­sent­ed at the 112^th An­nu­al Meet­ing of the Japan­ese Uro­log­i­cal As­so­ci­a­tion, April 19, 2025. Avail­able at: https://www.mi­ce­navi.jp/jua2025/search/de­tail_pro­gram/id:2055