More dra­ma ahead: Sarep­ta plans to file for ac­cel­er­at­ed Duchenne ap­proval, with ad­comm a 'n­ear cer­tain­ty'

29 Jul 2022
endpts.com
Accelerated Approval
While Sarep­ta has three an­ti­sense oligonu­cleotide ther­a­pies ap­proved — al­beit not with­out con­tro­ver­sy — for Duchenne mus­cu­lar dy­s­tro­phy, it has been work­ing on a long-term treat­ment in the form of a gene ther­a­py.
Af­ter post­ing pos­i­tive re­sults for its Roche-part­nered gene ther­a­py, dubbed SRP-9001, ear­li­er this month, the Cam­bridge, MA-based biotech says it now in­tends to pur­sue an ac­cel­er­at­ed ap­proval for its lat­est Duchenne treat­ment. Sarep­ta shares $SRPT rose about 10% on the news in ear­ly Fri­day trad­ing.
Baird an­a­lyst Bri­an Sko­r­ney wrote in a note that he be­lieved Sarep­ta is “well-aligned with the FDA on the plan to file this fall, with the po­ten­tial for an ap­proval de­ci­sion by mid-2023.” Sko­r­ney added:
Giv­en this pos­i­tive com­men­tary, we think that once the BLA is sub­mit­ted, around Oc­to­ber at the lat­est, FDA ac­cep­tance for re­view will be a near cer­tain­ty. Al­though man­age­ment not­ed they have not dis­cussed the pos­si­bil­i­ty of an Ad­vi­so­ry Com­mit­tee Meet­ing with the agency, they feel that an Ad­Com will be a near cer­tain­ty giv­en the grav­i­ty of the re­view, and we con­cur with this ex­pec­ta­tion.
Sko­r­ney al­so not­ed that the fil­ing may in­clude all am­bu­lant Duchenne pa­tients sans age re­stric­tions, though its cur­rent tri­als are in pa­tients ages 4-7.
In ear­ly 2021, SRP-9001 failed in an ini­tial Phase II study, which Sarep­ta at­trib­uted to dif­fer­ences in base­line mea­sures be­tween the old­er chil­dren of the place­bo and treat­ment groups. That fail cut the biotech’s stock $SRPT by half, where it has hov­ered since.
How­ev­er, in the sec­ond part of that Phase II study, in which 20 pa­tients who had re­ceived the place­bo treat­ment crossed over to get Sarep­ta’s gene ther­a­py, the pa­tients showed sta­tis­ti­cal­ly sig­nif­i­cant im­prove­ments in the mo­tor abil­i­ties test that was al­so used in Part 1.
Ear­li­er this month, Sarep­ta again post­ed pos­i­tive re­sults from oth­er parts of its gene ther­a­py pro­gram, show­ing that its gene ther­a­py sig­nif­i­cant­ly im­proved pa­tients’ mo­tor func­tion af­ter one year. But one pa­tient who had got­ten Sarep­ta’s gene ther­a­py ex­pe­ri­enced a case of my­ocardi­tis, or heart in­flam­ma­tion. No­tably, Pfiz­er’s Duchenne gene ther­a­py pro­gram al­so saw two cas­es of heart in­flam­ma­tion.
Pre­vi­ous­ly, the two com­pa­nies, along with Sol­id Bio­sciences and Genethon, sug­gest­ed those cas­es may be tied to a “class ef­fect.”
For its ac­cel­er­at­ed ap­proval, Sarep­ta plans to use both an in­ter­me­di­ate clin­i­cal end­point, the score on the func­tion­al mo­tor test af­ter one year, as well as a sur­ro­gate bio­mark­er, dy­s­trophin ex­pres­sion, a Sarep­ta spokesper­son told End­points News.
Pfiz­er, Sarep­ta and two oth­ers sug­gest Duchenne drug safe­ty is­sues tied to "class ef­fect"
Sarep­ta is no stranger to ac­cel­er­at­ed ap­provals, hav­ing got­ten them for its last three Duchenne mus­cu­lar dy­s­tro­phy treat­ments. Its first ac­cel­er­at­ed ap­proval came in 2016 for Ex­ondys 51, rife with con­tro­ver­sy.
Sev­er­al FDA of­fi­cials at the time were against the ap­proval of the drug, with one call­ing it a “sci­en­tif­i­cal­ly el­e­gant place­bo,” but were over­shad­owed by Janet Wood­cock, who ad­vo­cat­ed for its ap­proval.
“It set this in­ter­est­ing, slash con­cern­ing, prece­dent around dy­s­trophin as a val­i­dat­ed sur­ro­gate end­point, be­cause there’s not re­al­ly ev­i­dence of it ac­tu­al­ly hav­ing clear clin­i­cal as­so­ci­a­tion with things that are mean­ing­ful for as­sess­ing ben­e­fit (for) Duchenne mus­cu­lar dy­s­tro­phy,” Yale School of Med­i­cine pro­fes­sor Resh­ma Ra­machan­dran told End­points News.
Ra­machan­dran not­ed that Ex­ondys 51’s ap­proval al­so set the prece­dent for Sarep­ta’s two fol­low­ing ac­cel­er­at­ed ap­provals. Ac­cord­ing to the gov­ern­ment’s clin­i­cal tri­als web­site, Sarep­ta’s con­fir­ma­to­ry tri­als for its three an­ti­sense oli­go treat­ments are set to fin­ish in 2024 — some eight years af­ter its first ap­proval.
Sarep­ta’s lack of con­fir­ma­to­ry tri­al re­sults speaks to a big­ger pat­tern, in which com­pa­nies that get ac­cel­er­at­ed ap­provals drag their feet on con­fir­ma­to­ry tri­als or fail to do them at all, a prob­lem a bi­par­ti­san Sen­ate bill aims to re­form. In the com­ing weeks, Con­gress is like­ly to pass a bill that will broad­en the FDA’s au­thor­i­ty to en­sure con­fir­ma­to­ry stud­ies are un­der­way be­fore ac­cel­er­at­ed ap­proval is grant­ed.
Sen­ate un­veils its ver­sion of ac­cel­er­at­ed ap­proval re­forms as bi­par­ti­san duo calls on FDA and PTO to work to­geth­er
In­ter­est­ing­ly, in April, Sarep­ta moved up the time­line for Ex­ondys 51’s con­fir­ma­to­ry tri­al, dubbed MIS51ON, by about one and a half years, from ear­ly 2026 to late 2024. A Sarep­ta spokesper­son told End­points in an email the ear­li­er time­line re­flect­ed ad­di­tion­al tri­al sites.
Pfiz­er is al­so de­vel­op­ing a gene ther­a­py for Duchenne mus­cu­lar dy­s­tro­phy. While its Phase III tri­al was put on hold fol­low­ing a pa­tient death, the phar­ma gi­ant has since re­sumed the tri­al, it said in April. That tri­al is set to read out by late 2023.
UP­DAT­ED: Pfiz­er can restart PhI­II tri­al of Duchenne gene ther­a­py, now on track for late-2023 FDA ap­proval re­quest
No­tably, Sarep­ta is cur­rent­ly al­so run­ning a Phase III tri­al, dubbed EM­BARK, for its gene ther­a­py, and its end­point is the func­tion­al mo­tor test. How­ev­er, the es­ti­mat­ed com­ple­tion date for that Phase III tri­al cur­rent­ly stands at Oc­to­ber 2023, while Sarep­ta’s FDA ap­proval date could be ear­li­er in the year if it files for ac­cel­er­at­ed ap­proval this fall. The Sarep­ta spokesper­son con­firmed that Sarep­ta be­lieves EM­BARK would be the con­fir­ma­to­ry tri­al for SRP-9001’s ac­cel­er­at­ed ap­proval.
“Buck­le up, the next year is go­ing to be an in­ter­est­ing de­bate on Sarep­ta and the time­line around FDA ac­tion, what de­fines ‘rea­son­ably like­ly to pre­dict’, and how EM­BARK read­out im­pacts the time­frame for ac­tion,” Sko­r­ney wrote.
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