The US FDA’s Car­dio­vas­cu­lar and Re­nal Drugs Ad­vi­so­ry Com­mit­tee on Wednes­day vot­ed 13-0 that the agency should not ap­prove Rea­ta Phar­ma­ceu­ti­cals’ bar­dox­olone methyl cap­sules as a treat­ment to slow the pro­gres­sion of chron­ic kid­ney dis­ease in those with the rare Al­port syn­drome.

The lop­sided vote fol­lows sim­i­lar com­ments from FDA on Mon­day, which paint­ed an over­whelm­ing­ly neg­a­tive opin­ion on Rea­ta’s $RE­TA po­ten­tial drug, ac­cord­ing to brief­ing doc­u­ments re­leased ahead of to­day’s meet­ing.

Rea­ta’s stock price fell by an­oth­er 44% in af­ter-hours trad­ing, af­ter a pre­vi­ous 30+% drop ear­li­er in the week.

And ad­comm mem­bers large­ly agreed with the agency Wednes­day, say­ing safe­ty con­cerns gave them se­ri­ous pause, while tak­ing is­sue with the way Rea­ta ran its Phase III tri­al, and the com­plex­i­ty of the da­ta pre­sent­ed. Mem­bers of the com­mit­tee al­so sought clar­i­fi­ca­tions on why Rea­ta used eGFR as the main mea­sure for its Phase III, not­ing oth­er mea­sures might have been more in­for­ma­tive.

“FDA set the tone and the com­mit­tee re­sound­ing­ly agreed, dis­count­ing all of Rea­ta’s ar­gu­ments and leav­ing al­most ze­ro chance of ap­proval,” Baird biotech an­a­lyst Bri­an Sko­r­ney wrote in a note to in­vestors.

The use of eGFR, which is an es­ti­mate of the kid­ney’s fil­tra­tion rate, was meant to as­sess dis­ease pro­gres­sion, with Rea­ta ar­gu­ing that its Phase III showed pa­tients treat­ed with bar­dox­olone ex­pe­ri­enced a sta­tis­ti­cal­ly sig­nif­i­cant im­prove­ment in kid­ney func­tion as mea­sured by eGFR at Week 100 and Week 104, com­pared to pa­tients treat­ed with place­bo.

Near­ly every ad­comm mem­ber seemed to dis­agree with that con­clu­sion.

Pan­elist Paul Palevsky, chief of the kid­ney med­i­cine sec­tion at the VA Pitts­burgh Health­care Sys­tem, said that as much as he wants to see a drug that has an al­ter­na­tive mech­a­nism for im­prov­ing func­tion for this rel­a­tive­ly rare form of kid­ney dis­ease, he’s “quite con­cerned that the da­ta pro­vid­ed does not meet the bar of show­ing this will slow the time to end stage kid­ney dis­ease.”

Ad­comm mem­ber Patrick Nach­man, pro­fes­sor of med­i­cine at the Uni­ver­si­ty of Min­neso­ta, al­so ex­pressed wor­ries about the gen­er­al­iz­abil­i­ty of the da­ta pre­sent­ed, say­ing that the da­ta did not show ben­e­fit, but that he’s sen­si­tive to the idea there might be a group of pa­tients that could ben­e­fit from this treat­ment.

In the sum­ma­ry af­ter the first dis­cus­sion ques­tion of the meet­ing, chair of the ad­comm Ju­lia Lewis, pro­fes­sor of med­i­cine at Van­der­bilt, raised sev­er­al lin­ger­ing ques­tions too, like why on­ly en­roll 11 ado­les­cents in the Phase III if the spon­sor is seek­ing an in­di­ca­tion for an age group of 12 and up?

Pan­elist Su­san Mend­ley of the NIH’s Na­tion­al In­sti­tute of Di­a­betes and Di­ges­tive and Kid­ney Dis­eases al­so called on Rea­ta to study the drug more in the younger pop­u­la­tion as she’s con­cerned on the ef­fects of weight gain and growth out­weigh­ing the ben­e­fits.

Ad­comm mem­ber Gre­go­ry Gor­man, cap­tain in the med­ical corps of the US Navy, said that as a pe­di­atric nephrol­o­gist, he would’ve liked to hear that some pa­tient-re­port­ed out­come mea­sures were im­prov­ing. Oth­ers ques­tioned why the pa­tients were un­blind­ed to their GFR es­ti­mates, and how that could have bi­ased how they per­ceived their out­comes.

“I might have giv­en it the ben­e­fit of the doubt,” Gor­man said, but that’s nul­li­fied by bar­dox­olone’s safe­ty con­cerns, and even with the sta­tis­ti­cal­ly sig­nif­i­cant, small ef­fect, it might be nul­li­fied over the long term.

Orig­i­nal­ly de­vel­oped as a can­cer drug, bar­dox­olone was lat­er scut­tled by Rea­ta al­most a decade ago as a chron­ic kid­ney dis­ease drug due to deaths in a Phase III tri­al.

Rea­ta went back and ran the Phase III tri­al, which wrapped up four years ago, and on which this ap­pli­ca­tion is based.

Ed­i­tor’s note: Ar­ti­cle up­dat­ed with stock price re­ac­tion and com­ments from Baird’s Sko­r­ney.

As President Biden’s Build Back Better Act — and, with it, potentially the Democrats’ last shot at major drug pricing reforms in the foreseeable future — remains on life support, the Congressional Budget Office isn’t helping their case.

The CBO last week released a new slide deck, outlining an update to its model on how Medicare negotiations might take a bite out of new drugs making it to market. The new model estimates a 10% long-term reduction in the number of new drugs, whereas a previous CBO report from August estimated that 8% fewer new drugs will enter the market over 30 years.

While the US biosimilars industry has generally been a disappointment since its inception, with FDA approving 33 biosimilars since 2015, just a fraction of those have immediately followed their approvals with launches. And more than a handful of biosimilars for two of the biggest blockbusters of all time — AbbVie’s Humira and Amgen’s Enbrel — remain approved by FDA but still have not launched because of legal settlements.