When Fre­quen­cy Ther­a­peu­tics scored $80 mil­lion in cash from Astel­las to jump­start an al­liance, the biotech cau­tious­ly point­ed to Phase I/II da­ta bol­ster­ing hope that they might in­deed have a ground­break­ing re­gen­er­a­tive med­i­cine ap­proach to restor­ing hear­ing, lean­ing on re­search done by Bob Langer and Jeff Karp out of MIT around prog­en­i­tor cell ac­ti­va­tion.

New­ly re­leased Phase IIa re­sults are now keep­ing them away from that lofty goal.

David Lucchi­no

At the in­ter­im analy­sis, four week­ly in­jec­tions of FX-322 failed to im­prove things for pa­tients with mild to mod­er­ate­ly se­vere sen­sorineur­al hear­ing loss, whether they looked at word recog­ni­tion, words-in-noise, pure tone au­diom­e­try and ad­di­tion­al ex­plorato­ry or oth­er mea­sures.

Fre­quen­cy ex­ecs, though, be­lieve the blame lies not with the drug but with the tri­al de­sign. Armed with pre­lim­i­nary da­ta from a sep­a­rate Phase I/II tri­al, they are all but giv­ing up on the four-dose reg­i­men and go­ing back to take a sin­gle-shot ap­proach through fur­ther eval­u­a­tion in­stead — with lessons tak­en from the lat­est mid-stage tri­al.

“I can tell you that we have tak­en a mean­ing­ful step clin­i­cal­ly, though not in the way we an­tic­i­pat­ed,” CEO David Lucchi­no said in an in­vestor call.

Cowen an­a­lyst Phil Nadeau was sym­pa­thet­ic to the ar­gu­ment, not­ing that while the topline read­out brings the bi­o­log­ic ef­fect of the drug in­to ques­tion, Fre­quen­cy may have a point in con­tin­u­ing its de­vel­op­ment:

We agree that the repli­ca­tion of the ini­tial sin­gle dose da­ta sug­gest that ‘322’s pro­file should con­tin­ue to be ex­plored. Though there are nu­mer­ous caveats to sin­gle arm stud­ies (most no­tably the con­tralat­er­al ear in study ‘111 need not have WR deficits at base­line) the con­sis­ten­cy of ef­fect in the two tri­als pro­vides a sig­nal of ef­fi­ca­cy for the sin­gle in­jec­tion reg­i­mens.

In­vestors are less cheery, tank­ing the shares 77.98% Tues­day af­ter­noon.

The first of two main is­sues, Lucchi­no ex­plained, was that the four week­ly in­jec­tions seemed to “tem­porar­i­ly over­whelm the ear.”

“This is a bit of an over­sim­pli­fied anal­o­gy, but one that can pos­si­bly fit: When you re­seed the lawn, you need to stay off the grass,” he said. “In oth­er words, while we can’t see the pre­cise mech­a­nisms in play, mul­ti­ple week­ly in­jec­tions led to con­di­tions that did not al­low FX-322 to achieve its in­tend­ed ef­fect.”

Sec­ond­ly, he im­plied that some pa­tients may have ex­ag­ger­at­ed the ex­tent of their word recog­ni­tion deficit in or­der to get in­to the study, re­sult­ing in an un­ex­pect­ed­ly high lev­el of hear­ing ben­e­fit in the place­bo group — “out­liers” that his team had nev­er seen be­fore.

In the tri­al, all 95 par­tic­i­pants re­ceived four in­jec­tions to­tal, with dif­fer­ent com­bi­na­tions of drug and place­bo. None of the treat­ment groups had dis­cernible ben­e­fit com­pared to place­bo.

The rea­son Fre­quen­cy is hold­ing out hope comes most­ly from pre­lim­i­nary re­sults in an open-la­bel study in which a sin­gle dose of FX-322 was giv­en to 33 pa­tients with se­vere SNHL. With the un­treat­ed ear as the con­trol, in­ves­ti­ga­tors re­port­ed that 34% of par­tic­i­pants saw a 10% or greater im­prove­ment in word recog­ni­tion scores. A sub­set even more than dou­bled their WR scores.

Two oth­er ear­ly-stage, place­bo-con­trolled tri­als on the sin­gle in­jec­tion are on­go­ing, fo­cus­ing on age-re­lat­ed hear­ing loss and se­vere SNHL, re­spec­tive­ly. Re­sults should be in lat­er this year — when Fre­quen­cy al­so ex­pects to re­port fi­nal num­bers from the flopped Phase IIa.

“We rec­og­nized when we start­ed and con­tin­ue to rec­og­nize to­day that achiev­ing such a bold goal would not be with­out un­ex­pect­ed turns along the way,” Lucchi­no said. “We be­lieve in the tech­nol­o­gy, we be­lieve in the da­ta, and we will fol­low the sci­ence.”

DC District Court Judge Christopher Cooper today granted Vanda Pharma’s request to require the FDA to disclose more info on the complete response letter for its sleep disorder drug Hetlioz.

The melatonin receptor agonist is approved by the FDA to treat non-24-hour sleep-wake disorder, a circadian rhythm disorder. But in 2018 Vanda filed a supplemental application to market Hetlioz as a treatment for jet lag, which the FDA rejected in August 2019, with few details on what Vanda needed to correct course, according to the company.

Codiak BioSciences has filed for Chapter 11 bankruptcy, spelling an end to the employment of most executives, including founder Doug Williams, as the biotech says it “expects to consummate a sale.”

The eight-year journey at Codiak is nearing an end with Williams; CFO Linda Bain; medical chief David Mauro; scientific head Sriram Sathyanarayanan; legal and compliance chief Yalonda Howze; and SVP of HR Nicole Barna all packing up their bags in the first few days of April. Chief technology officer Konstantin Konstantinov will stay.