Glass half emp­ty: Achao­gen re­ceives split vote from FDA ex­perts on lead an­tibi­ot­ic, shares plunge

An FDA ad­vi­so­ry com­mit­tee has hand­ed down a split vote — yes for one in­di­ca­tion and no for an­oth­er — on Achao­gen’s lead an­tibi­ot­ic, ruf­fling the high ex­pec­ta­tions it set up go­ing in.

In­vestors weren’t hap­py, send­ing Achao­gen stocks down close to 29% in af­ter-hours trad­ing.

The split de­ci­sion car­ries in­ter­est­ing im­pli­ca­tions for oth­er an­tibi­ot­ic mak­ers. In a first, Achao­gen $AKAO sub­mit­ted an NDA with a re­quest to use the Lim­it­ed Pop­u­la­tion An­tibac­te­r­i­al Drug (LPAD) path­way in re­view­ing the drug, pla­zomicin, for the treat­ment of blood­stream in­fec­tions (BSI) due to Car­bapen­em-re­sis­tant En­ter­obac­te­ri­aceae. That hap­pens to be the in­di­ca­tion that the ad­comm vot­ed down; all 15 of them vot­ed yes when it came to treat­ing pa­tients with com­pli­cat­ed uri­nary tract in­fec­tions (cU­TI).

Pack­aged in­to the 2016 21th Cen­tu­ry Cures Act, the LPAD reg­u­la­to­ry path­way al­lows for ac­cep­tance of greater un­cer­tain­ty or high­er risk in pa­tients with se­ri­ous dis­eases (and an un­met need) pro­vid­ed that sub­stance ev­i­dence of ef­fec­tive­ness is pre­sent­ed.

A large part of what seems to have doomed Achao­gen’s plans for the BSI in­di­ca­tion was a small­er-than-ex­pect­ed sam­ple size that com­pli­cat­ed sta­tis­ti­cal analy­sis. Ear­ly in the meet­ing, an FDA clin­i­cal re­view­er point­ed out that the biotech had to amend pro­to­cols for a Phase III study (ACHN-490-007) be­cause they could on­ly en­roll 37 pa­tients out of the 286 planned. That re­sult­ed in sta­tis­ti­cal lim­i­ta­tions in con­clud­ing that pla­zomicin had su­pe­ri­or ef­fi­ca­cy com­pared to col­istin in the com­para­tor arm, even though nu­mer­i­cal trends point­ed to that con­clu­sion.

The re­view­er went on to sug­gest look­ing at the da­ta through the lens of non­in­fe­ri­or­i­ty, which the da­ta would al­low for, but cau­tioned that such as­sess­ments are com­pli­cat­ed by de­sign fea­tures the FDA agreed to back when Achao­gen was plan­ning a su­pe­ri­or­i­ty tri­al. Among those fea­tures: pri­or or con­comi­tant an­tibac­te­r­i­al ther­a­py, as well as lax­er cri­te­ria for pa­tients re­gard­ing bac­te­ria cul­ture in their bod­ies. That ad­di­tion­al un­cer­tain­ty re­gard­ing base­line sta­tus for pa­tients didn’t help, ei­ther.

Af­ter dis­cussing the sta­tis­ti­cal plan and clar­i­fy­ing how best to bal­ance the LPAD con­sid­er­a­tion with ben­e­fit-risk as­sess­ments, 11 com­mit­tee mem­bers vot­ed against pla­zomicin in BSI, most­ly con­cerned that the study was un­der­pow­ered to sup­port con­clu­sions of ef­fi­ca­cy. The oth­er four dis­agreed, cit­ing the lim­it­ed use and un­met need.

For cU­TI, on the oth­er hand, com­mit­tee mem­bers had no prob­lem unan­i­mous­ly en­dors­ing pla­zomicin based on a study that showed its was non­in­fe­ri­or to meropen­em, even con­sid­er­ing a larg­er mar­gin of 15% (ver­sus a con­ven­tion­al 10%) the FDA sanc­tioned.

Achao­gen CEO Blake Wise had this to say in a short state­ment:

We are en­cour­aged by the Com­mit­tee’s unan­i­mous vote in fa­vor of pla­zomicin for com­pli­cat­ed uri­nary tract in­fec­tions (cU­TI). The dis­cus­sion un­der­scored the re­al-world chal­lenges that health­care providers face every day giv­en lim­it­ed or in­ad­e­quate treat­ment op­tions for cer­tain pathogens. Re­gard­ing blood­stream in­fec­tions, the Lim­it­ed-Pop­u­la­tion An­tibac­te­r­i­al Drug path­way, or LPAD, is a nov­el ap­proach that en­ables the FDA to con­sid­er the ben­e­fits and risks for the sick­est pa­tients who have few or no avail­able treat­ment op­tions, and to ap­prove an­tibi­otics like pla­zomicin that we be­lieve, have the po­ten­tial to ad­dress these lim­it­ed pa­tient pop­u­la­tions.

South San Fran­cis­co-based Achao­gen is one of a hand­ful of biotechs in late-stage de­vel­op­ment with new an­tibi­otics in an era of ris­ing drug re­sis­tance to the main­stays in the field. Whether it will be­come a trail­blaz­er or a cau­tion­ary tale will be­come clear by its PDU­FA date of June 25.

Tesla and SpaceX founder Elon Musk gestures to the audience after being recognized by President Trump following the successful launch of a Falcon 9 rocket at the Kennedy Space Center. (via Getty Images)

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Elias Zerhouni (Photo by Vincent Isore/IP3/Getty Images)

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Vas Narasimhan, Novartis CEO (Patrick Straub/​EPA-EFE/​Shutterstock)

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