Ad­comm splits slight­ly in fa­vor of FDA ap­prov­ing Chemo­Cen­tryx’s rare dis­ease drug

The FDA’s Arthri­tis Ad­vi­so­ry Com­mit­tee on Thurs­day vot­ed 10 for and 8 against the ap­proval of Chemo­Cen­tryx’s $CCXI in­ves­ti­ga­tion­al drug ava­co­pan as a treat­ment for adults with a rare and se­ri­ous dis­ease known as an­ti-neu­trophil cy­to­plas­mic au­toan­ti­body (AN­CA)-vas­culi­tis.

The vote on whether the FDA should ap­prove the drug was pre­ced­ed by a split vote of 9 to 9 on whether the ef­fi­ca­cy da­ta sup­port ap­proval, and 10 to 8 that the safe­ty pro­file of ava­co­pan is ad­e­quate enough to sup­port ap­proval.

John Sperati

There was a con­tentious de­bate over whether the one, rel­a­tive­ly small Phase III tri­al com­par­ing ava­co­pan with pred­nisone was ro­bust enough for a full ap­proval. FDA raised con­cerns about the sta­tis­ti­cal analy­ses of the da­ta in the tri­al and what ef­fect the use of glu­co­cor­ti­coids on top of cy­clophos­phamide or rit­ux­imab in both treat­ment arms had on the ava­co­pan ef­fi­ca­cy. Chemo­Cen­tryx de­fend­ed its tri­al de­sign and ex­plained how it met its pri­ma­ry end­point and showed a re­duc­tion in the use of steroids with ava­co­pan.

Those vot­ing against ap­proval raised con­cerns about re­ly­ing on the sin­gle tri­al as ev­i­dence, the in­suf­fi­cient amount of safe­ty da­ta, and ques­tions on whether the tri­al was sta­tis­ti­cal­ly ro­bust enough. Some pan­elists called for Chemo­Cen­tryx to run an­oth­er tri­al.

AAC pan­elist John Sperati, as­so­ciate pro­fes­sor of med­i­cine at Johns Hop­kins Uni­ver­si­ty School of Med­i­cine, vot­ed no on whether the FDA should ap­prove the drug and said he had con­cerns with the study de­sign and per­sua­sive­ness of the da­ta. He ex­plained how if ava­co­pan is ap­proved by the FDA, one would have to use it in a sim­i­lar fash­ion as in the tri­al, but where its true ef­fi­ca­cy lies re­mains un­clear from that tri­al da­ta.

Ju­lia Lewis

An­oth­er pan­elist Ju­lia Lewis, pro­fes­sor of med­i­cine at Van­der­bilt Uni­ver­si­ty Med­ical Cen­ter, al­so vot­ed against ap­proval and said the in­di­ca­tion is too broad and far ex­ceeds the da­ta pre­sent­ed.

Those vot­ing in fa­vor of ap­proval not­ed that the tri­al just cleared the bar to meet its pri­ma­ry end­point and that tri­als in this pop­u­la­tion are dif­fi­cult to con­duct.

AAC pan­elist Wal­ter Kraft, pro­fes­sor of med­i­cine and surgery at Sid­ney Kim­mel Med­ical Col­lege of Thomas Jef­fer­son Uni­ver­si­ty, vot­ed for ava­co­pan to be ap­proved, say­ing reg­u­la­to­ry de­ci­sions are not made in a vac­u­um, but with ex­ist­ing ther­a­peu­tics in mind, and that the tri­al met its goal. He al­so raised con­cerns about de­lays in ac­cess to ava­co­pan if the FDA re­quires an ad­di­tion­al tri­al.

Fel­low pan­elist Margrit Wiesen­dan­ger, as­so­ciate pro­fes­sor at Ic­ahn School of Med­i­cine at Mount Sinai, al­so vot­ed in fa­vor of ap­prov­ing the drug, but said ju­di­cious use of it will be war­rant­ed and ad­di­tion­al guid­ance will be nec­es­sary to ex­plain who ex­act­ly should re­ceive it.

Wal­ter Kraft

Those vot­ing in fa­vor of ap­proval fol­lowed a se­ries of con­cerns raised by FDA sta­tis­ti­cal re­view­er Yu­ra Kim on the com­pa­ny’s as­sess­ments of the da­ta, not­ing, “Sta­tis­ti­cal analy­ses of the pri­ma­ry end­point us­ing the In­ves­ti­ga­tor as­sess­ment of BVAS [a clin­i­cal scor­ing sys­tem of dis­ease ac­tiv­i­ty to iden­ti­fy ac­tive vas­culi­tis in nine or­gan sys­tems] re­mis­sion re­sult­ed in small­er mag­ni­tude of treat­ment ef­fect and would not sup­port su­pe­ri­or­i­ty of ava­co­pan.”

The agency al­so ques­tioned if the oth­er drugs used in the study may have con­tributed to the ef­fi­ca­cy seen for ava­co­pan.

“In this case, both treat­ment arms re­ceived back­ground ther­a­py in the form of cy­clophos­phamide or rit­ux­imab. The ben­e­fit of glu­co­cor­ti­coids on top of cy­clophos­phamide or rit­ux­imab is not well un­der­stood,” Kim said. “As a re­sult, it is dif­fi­cult to de­ter­mine if sim­i­lar re­mis­sion rates ob­served on both arms can sup­port a con­clu­sion that ava­co­pan is ef­fec­tive or if sim­i­lar­i­ties can be pri­mar­i­ly at­trib­uted to both arms re­ceiv­ing rit­ux­imab or cy­clophos­phamide.”

Margrit Wiesen­dan­ger

The com­pa­ny de­fend­ed its study de­sign, not­ing that when rit­ux­imab won ap­proval in this in­di­ca­tion, it was pri­mar­i­ly based on re­sults from a sin­gle tri­al of about 200 pa­tients, and was de­signed as a non-in­fe­ri­or­i­ty, com­para­tor tri­al over 26 weeks.

Fol­low­ing that lead, Chemo­Cen­tryx in Ju­ly 2016 ini­tial­ly pro­posed a 26-week ran­dom­ized, dou­ble-blind tri­al com­par­ing ava­co­pan to pred­nisone in 232 pa­tients re­ceiv­ing ei­ther rit­ux­imab or cy­clophos­phamide, Pirow Bekker, the clin­i­cal lead for the ava­co­pan clin­i­cal de­vel­op­ment pro­gram, ex­plained.

The Eu­ro­pean Med­i­cines Agency agreed to the non-in­fe­ri­or­i­ty study, ac­cord­ing to Bekker, with the demon­stra­tion of su­pe­ri­or­i­ty in a sec­ondary end­point, such as glu­co­cor­ti­coid tox­i­c­i­ty.

But in the US, FDA said a 26-week non-in­fe­ri­or­i­ty study was not suf­fi­cient, he not­ed. In or­der to ad­dress both FDA and EMA’s feed­back, Chemo­Cen­tryx re­vised the study to be a 52-week study in about 300 pa­tients, with the su­pe­ri­or­i­ty as­sess­ment built in as well.

FDA’s Rachel Glaser con­firmed that there was an ex­pec­ta­tion agreed to in the pre-sub­mis­sion dis­cus­sions that su­pe­ri­or­i­ty would need to be con­firmed for ava­co­pan and that non-in­fe­ri­or­i­ty would not be enough.

The FDA is not re­quired to fol­low the ad­vice of its ad­vi­so­ry com­mit­tee on Chemo­Cen­tryx’s ava­co­pan, but in gen­er­al, the agency usu­al­ly does.

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