FDA ad­comm votes 12-1 against Le­vo Ther­a­peu­tic­s' nasal spray for a dis­or­der that caus­es in­sa­tiable hunger

The FDA’s Psy­chophar­ma­co­log­ic Drugs Ad­vi­so­ry Com­mit­tee on Thurs­day vot­ed 12 to 1 against ap­prov­ing Le­vo Ther­a­peu­tics’ nasal spray for Prad­er-Willi syn­drome, a dif­fi­cult-to-treat dis­ease that leaves pa­tients with con­stant, in­sa­tiable hunger.

Those who vot­ed no raised con­cerns about a lack of sub­stan­tial ev­i­dence, as a 9.6 mg dose of the drug failed the pri­ma­ry end­points in a Phase III tri­al. Look­ing for a sil­ver lin­ing, Le­vo turned to a 3.2 mg dose which met the tri­al’s sec­ondary end­points. But ad­comm mem­bers won­dered whether Le­vo could repli­cate those pos­i­tive re­sults.

“The thing that stuck out to me most was that the 9.6 dose study did not repli­cate,” com­mit­tee mem­ber Satish Iyen­gar, chair of the Uni­ver­si­ty of Pitts­burgh’s sta­tis­tics de­part­ment, said af­ter the vote. “And giv­en the fact that the 3.2 dose study didn’t re­al­ly hold up strong­ly to the sen­si­tiv­i­ty analy­sis that they did, I just have no con­fi­dence — I have lit­tle con­fi­dence — that it will repli­cate.”

An­oth­er pan­el mem­ber, UCLA psy­chi­a­try pro­fes­sor Wal­ter Dunn, sug­gest­ed that if the ques­tion had asked about “mod­er­ate ev­i­dence of ef­fec­tive­ness,” he would have re­con­sid­ered his vote.

“I do think it’s in­ter­est­ing that this is word­ed this way, be­cause it doesn’t talk at all about any pos­si­ble risk-ben­e­fit trade-off,” said James Troen­dle, a math­e­mat­i­cal sta­tis­ti­cian at the NIH.

Le­vo’s can­di­date, dubbed LV-101, is an in­tranasal form of car­be­tocin, a drug used out­side the US to con­trol bleed­ing af­ter child­birth. It’s an oxy­tocin re­cep­tor ag­o­nist that was orig­i­nal­ly be­ing de­vel­oped for PWS by Fer­ring Phar­ma­ceu­ti­cals, un­til Le­vo snagged the rights in 2016. Oxy­tocin is a neu­ro­trans­mit­ter that reg­u­lates so­cial-emo­tion­al and feed­ing be­hav­iors, and re­search shows that those with PWS don’t have enough of it.

But de­spite what Fer­ring cel­e­brat­ed as pos­i­tive Phase II re­sults, Le­vo faced an up­hill bat­tle. Al­though the car­be­tocin arm showed sta­tis­ti­cal­ly sig­nif­i­cant im­prove­ments over place­bo, the FDA called the da­ta weak and the study du­ra­tion in­suf­fi­cient. Then, last Au­gust, Le­vo an­nounced the 9.6 mg dose failed the pri­ma­ry end­points in a Phase III study: changes in base­line in ei­ther Hy­per­pha­gia Ques­tion­naire for Clin­i­cal Tri­als scores (HQ-CT) or Chil­dren’s Yale-Brown Ob­ses­sive-Com­pul­sive Scale (CY-BOCS) scores.

Hy­per­pha­gia is an­oth­er term for the ex­treme hunger ex­pe­ri­enced by PWS pa­tients. Re­searchers de­scribe it as a con­stant feel­ing of star­va­tion, adding that pa­tients will of­ten­times seek food wher­ev­er they can get it. As there are no cur­rent­ly ap­proved treat­ments, pa­tients cope by lim­it­ing the type and amount of food they con­sume, and in some cas­es even lock­ing re­frig­er­a­tor doors and trash bins.

Le­vo ap­proached the FDA with its 3.2 mg dose, which achieved sta­tis­ti­cal sig­nif­i­cance as eval­u­at­ed by the HQ-CT scores in the Phase III tri­al. How­ev­er, there was no mean­ing­ful dif­fer­ence seen in CY-BOCS scores. In their brief­ing ahead of the ad­comm, the FDA not­ed that the sec­ondary end­point met with the 3.2 mg dose “must be con­sid­ered in the con­text of the lack of ef­fi­ca­cy of the high­er dose (9.6 mg).”

Le­vo sug­gest­ed that the lack of ef­fi­ca­cy seen in the 9.6 mg group may have been due to off-tar­get va­so­pressin ef­fects emerg­ing with longer treat­ment du­ra­tion.

How­ev­er, the FDA wrote: “If that were the case, one would ex­pect to see a nom­i­nal dif­fer­ence ver­sus place­bo at Week 2 (con­sis­tent with the find­ings from Study 114); how­ev­er, no dif­fer­ence be­tween groups was ob­served at that ear­li­er time point.”

PWS has proved ex­treme­ly dif­fi­cult to treat. Mil­len­do Ther­a­peu­tics’ lead drug liv­o­le­tide failed a piv­otal tri­al for the treat­ment of PWS last April, send­ing shares plum­met­ing. The drug didn’t im­prove hy­per­pha­gia or oth­er eat­ing-re­lat­ed be­hav­iors. And Zaf­gen’s ZGN-1258, its sec­ond at­tempt to treat rare cas­es of obe­si­ty brought on by PWS, hit a brick wall af­ter the FDA put a hold on the com­pa­ny’s PWS pro­gram in 2018, cit­ing CV safe­ty con­cerns.

Mul­ti­ple par­ents of chil­dren with PWS tuned in to the ad­comm meet­ing, tout­ing car­be­tocin as a mir­a­cle that has al­lowed their chil­dren to fi­nal­ly sleep through the night, or vis­it Dis­ney World with­out ob­sess­ing over food.

“You have the op­por­tu­ni­ty to change and pos­si­bly save an un­told num­ber of lives. Please take it,” one par­ent said.

But mul­ti­ple oth­ers ar­gued against the drug, with one par­ent call­ing it “com­plete­ly use­less” and even claim­ing the treat­ment wors­ened her child’s be­hav­ior.

Al­ice Shap­ley, a pa­tient rep­re­sen­ta­tive and the on­ly ad­comm mem­ber who vot­ed in sup­port of the drug, said: “In light of the promis­ing safe­ty pro­file of car­be­tocin, I’m con­vinced of the high ra­tio of ben­e­fit to risk for this treat­ment for the PWS com­mu­ni­ty.”

Charles Billing­ton, an en­docri­nol­o­gist and pro­fes­sor of med­i­cine at the Uni­ver­si­ty of Min­neso­ta, said he was moved by the com­pelling sto­ries by fam­i­ly mem­bers. But when it comes down to whether there’s sub­stan­tial ev­i­dence to back the drug, the an­swer is no.

“It’s hard to find any ev­i­dence of a sig­nal at all,” he said.

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