In a damn­ing in­dict­ment, FDA re­view scorns PTC’s Duchenne drug for re­peat­ed fail­ures

PTC Ther­a­peu­tics $PTCT ex­ec team proved this week that they are glut­tons for pun­ish­ment.

PTC Ther­a­peu­tics CEO Stu­art Peltz

Af­ter en­dur­ing two hu­mil­i­at­ing slap-downs at the FDA for their would-be Duchenne drug ataluren, the biotech — led by CEO Stu­art Peltz — has forced the agency’s hand, re­quir­ing a pan­el re­view on Thurs­day. And in the agency’s re­view of the drug, re­leased Tues­day morn­ing, the FDA went to con­sid­er­able lengths to ex­plain why they think this drug — pro­vid­ed an ac­cel­er­at­ed ap­proval in Eu­rope, where it’s sold to pa­tients as Translar­na — has re­peat­ed­ly proved to be un­wor­thy of an ap­proval.

PTC shares slid 23% af­ter the re­view land­ed, prov­ing that there are still clear lines on ef­fi­ca­cy that the FDA will not cross.

The sum­ma­ry says it all. Reg­u­la­tors at the FDA re­it­er­at­ed a se­ries of damn­ing con­clu­sions, with no pos­i­tive da­ta to con­sid­er. PTC’s post hoc analy­ses of failed stud­ies, they con­clud­ed, are un­con­vinc­ing in light of the fact that the re­sults were “clear­ly neg­a­tive”, while high­light­ing the “mis­lead­ing na­ture of ex­plorato­ry analy­ses of neg­a­tive tri­als.” And there’s no rea­son to be­lieve that any fu­ture tri­als of this drug will prove it can be ef­fec­tive.

In full, the FDA stat­ed:

Ul­ti­mate­ly, no pos­i­tive re­sults from any prospec­tive­ly planned analy­ses that are per­sua­sive have been pro­vid­ed with this ap­pli­ca­tion. The ap­pli­cant has pre­sent­ed on­ly the re­sults from nu­mer­ous post hoc and ex­plorato­ry analy­ses that are in­tend­ed to mit­i­gate two neg­a­tive clin­i­cal tri­als. In 2011, the ap­pli­cant claimed that the ef­fec­tive­ness of ataluren had been es­tab­lished based on the post hoc analy­ses of the ADP pop­u­la­tion in Study 007. How­ev­er, when this con­clu­sion was prospec­tive­ly eval­u­at­ed in Study 020, the re­sults were clear­ly neg­a­tive. This find­ing di­rect­ly high­lights the fre­quent­ly mis­lead­ing na­ture of ex­plorato­ry analy­ses of neg­a­tive tri­als. It is ar­guable that some trends ob­served in the ap­pli­cant’s da­ta may war­rant fur­ther prospec­tive in­ves­ti­ga­tion, which the Agency has con­sis­tent­ly en­cour­aged the ap­pli­cant to con­sid­er. Even so, for the rea­sons dis­cussed above, it seems quite pos­si­ble that any fu­ture study de­signed based on ex­plorato­ry analy­ses of Study 020 will al­so turn out to be neg­a­tive, just as Study 020, which was based on ex­plorato­ry post hoc analy­ses from Study 007, was neg­a­tive. The anal­o­gous re­sults from the ap­pli­cant’s de­vel­op­ment of ataluren for the treat­ment of nm­CF of­fer a sim­i­lar cau­tion­ary tale. Over­all, the da­ta in­tend­ed by the ap­pli­cant to es­tab­lish the ef­fec­tive­ness of ataluren for the treat­ment of nmD­MD are not per­sua­sive.

That qual­i­fies as one of the most con­clu­sive re­jec­tions I’ve seen of any drug ap­pli­ca­tion at the FDA. Pos­si­bly PTC was em­bold­ened by the agency’s ac­cel­er­at­ed OK of Sarep­ta’s drug, even though the com­pa­ny nev­er pro­vid­ed da­ta that the drug could work. In this case, though, the agency feels they have plen­ty of da­ta to con­clude that ataluren doesn’t work. And there’s no ev­i­dence to sug­gest that Janet Wood­cock will be rid­ing to PTC’s de­fense. Even a big show­ing of sup­port from Duchenne par­ents Thurs­day may prove un­like­ly to tip the scales in PTC’s fa­vor.

PTC, though, con­tin­ues to push ahead in DMD, re­gard­less of the crit­i­cism that has been lev­eled against it. That was proved again af­ter the com­pa­ny bought out  a cheap, old Eu­ro­pean steroid — de­flaza­cort — from Marathon Phar­ma­ceu­ti­cals af­ter Marathon ex­ecs de­cid­ed to bag it and flee from the in­tense re­ac­tion to their plans to price it at $89,000 list af­ter gain­ing the agency’s OK. PTC is now sell­ing de­flaza­cort at an even high­er rate for some of the old­er, larg­er boys suf­fer­ing from DMD af­ter par­ents had been able to source it abroad for about $1,000 a year.

Eu­ro­pean reg­u­la­tors have re­peat­ed­ly giv­en PTC a pass with their drug. And there’s no in­di­ca­tion that even a damn­ing re­sponse like this will change their po­si­tion.

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Vas Narasimhan. Getty Images

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