A split ad­vi­so­ry pan­el vote on Durect’s non-opi­oid drug to man­age post-sur­gi­cal pain is on­ly go­ing to make the FDA’s task hard­er.

Af­ter FDA staff re­view­ers is­sued an in­ter­nal re­view that un­der­scored their un­ease with the side-ef­fect pro­file of the long-act­ing anes­thet­ic posimir — on Thurs­day a pan­el of in­de­pen­dent ex­perts could not reach a con­sen­sus on whether to back the ther­a­py.

Six pan­elists en­dorsed ap­proval, while the re­main­ing six dis­sent­ed. The ther­a­py is a for­mu­la­tion of the anes­thet­ic bupi­va­caine and is de­signed to man­age pain up to three days fol­low­ing surgery af­ter be­ing ad­min­is­tered di­rect­ly in­to the sur­gi­cal in­ci­sion.

Posimir has a check­ered past. Durect, which orig­i­nal­ly part­nered with No­var­tis on the pro­gram, first sub­mit­ted an ap­pli­ca­tion to mar­ket on the ba­sis of two piv­otal stud­ies. The FDA spurned the ap­pli­ca­tion in 2014 over safe­ty con­cerns. Durect then con­duct­ed the PER­SIST study, hop­ing to quell the agency’s con­cerns — but that tri­al failed its main ef­fi­ca­cy goal. Nonethe­less, Durect re­sub­mit­ted a mar­ket­ing ap­pli­ca­tion.

Joseph O’Brien

The US drug reg­u­la­tor has in­ten­si­fied its ef­forts to stem the tide of opi­oid abuse, over­dose, and ad­dic­tion, fierce­ly scru­ti­niz­ing the phar­ma­ceu­ti­cal ar­chi­tects of the pre­scrip­tion painkiller cri­sis. So de­spite per­sis­tent safe­ty con­cerns as­so­ci­at­ed with posimir, the prospect of ‘opi­oid-spar­ing’ was ap­peal­ing to some pan­elists.

“The da­ta was in­con­sis­tent and there are some un­knowns that don’t make sense with the ra­tio­nale I heard,” said Joseph O’Brien, chief of Mass­a­chu­setts-based Na­tion­al Sco­l­io­sis Foun­da­tion, who en­dorsed posimir.”De­spite all these con­cerns, at the end of the day, we do have a need for opi­oid-spar­ing med­ica­tion,” he said, as cit­ed by Reuters.

Pan­elists against ap­proval ex­pressed their un­ease with posimir’s ef­fi­ca­cy, with some sug­gest­ing the ther­a­py’s du­ra­tion of ac­tion was lim­it­ed to 12 to 24 hours, echo­ing the FDA staff re­view is­sued on Tues­day. Con­cerns about safe­ty lin­gered with pan­elists on ei­ther side of the vote, and some sug­gest­ed ad­di­tion­al stud­ies were war­rant­ed to demon­strate res­cue in the event of ac­ci­den­tal in­tra­venous ad­min­is­tra­tion.

A 50/50 split vote is rare. Last year, a pill for pa­tients with the less com­mon type 1 di­a­betes, who pro­duce no in­sulin, was the sub­ject of an atyp­i­cal hung ju­ry vote at an FDA pan­el. Ex­perts were di­vid­ed even­ly over whether the life-threat­en­ing risk of di­a­bet­ic ke­toaci­do­sis as­so­ci­at­ed with the drug, so­tagliflozin, off­set its ben­e­fit — the FDA even­tu­al­ly re­ject­ed the di­a­betes ther­a­py.

Some pan­elists de­lib­er­at­ing on posimir seemed more open to con­sid­er­ing the ther­a­py’s da­ta as ev­i­dence of opi­oid-spar­ing com­pared to a No­vem­ber 2018 Ad­Com on opi­oid-spar­ing end­points, Cowen’s Boris Peak­er wrote in a note, which drew com­par­isons be­tween posimir and two oth­er bupi­va­caine painkillers: HTX-011 from Heron $HRTX and Ex­par­el from Paci­ra $PCRX.

“De­spite the ques­tion­able da­ta, the ‘yes’ votes were pri­mar­i­ly dri­ven by the time to opi­oid res­cue da­ta,” Peak­er wrote. “If time to opi­oid res­cue does be­come a sig­nif­i­cant end­point, HRTX’s da­ta ap­pears to be stronger than PCRX in cross-tri­al com­par­i­son. As such, we see this as an­oth­er op­por­tu­ni­ty for HTX-011 dif­fer­en­ti­a­tion vs. Ex­par­el.”

Paci­ra’s J&J-part­nered, long-act­ing post-op bupi­va­caine painkiller Ex­par­el gen­er­at­ed net sales of about $331 mil­lion in 2018. Heron’s HTX-011 — a for­mu­la­tion of bupi­va­caine and the non-steroidal an­ti-in­flam­ma­to­ry drug (NSAID) meloxi­cam — re­ceived an un­ex­pect­ed re­jec­tion due to man­u­fac­tur­ing con­cerns last year, but is on track to se­cure ap­proval by March.

Ear­li­er in the week, af­ter an FDA ad­vi­so­ry com­mit­tee vot­ed unan­i­mous­ly against Nek­tar Ther­a­peu­tics opi­oid painkiller — a for­mu­la­tion not en­gi­neered to fa­cil­i­tate abuse de­ter­rence from phys­i­cal ma­nip­u­la­tion — the com­pa­ny aban­doned the drug.

By Mwango Kashoki, MD, MPH, Vice President-Technical, and Richard Macaulay, Senior Director, of Parexel Regulatory & Access

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