Mike Garrett, Flamingo

Io­n­is col­lab­o­ra­tor Flamin­go is ready to take flight with 3 an­ti­sense drugs in the clin­ic and mys­te­ri­ous RNA in its sights

As the biggest name in an­ti­sense tech­nol­o­gy, Io­n­is has long fo­cused on test­ing the in­ter­play be­tween oligonu­cleotides and RNA for ther­a­peu­tic ef­fect. But one class of RNA has most­ly stumped re­searchers — un­til now.

Flamin­go Ther­a­peu­tics of­fi­cial­ly de­buted Thurs­day with three clin­i­cal and one pre­clin­i­cal can­cer drugs hand­ed off from an­ti­sense gu­ru Io­n­is, and an in­trigu­ing if un­proven dis­cov­ery en­gine gun­ning for mys­te­ri­ous long non-cod­ing RNA tar­gets.

It’s not com­mon to see a biotech launch with three clin­i­cal drugs in the fold, but Flamin­go’s short his­to­ry and close re­la­tion­ship with Io­n­is puts it in a unique po­si­tion for suc­cess. The com­pa­ny was found­ed in 2019 with some time in in­cu­ba­tion be­fore that, and it was co-found­ed by the re­search in­sti­tute VIB, Ghent Uni­ver­si­ty, KU Leu­ven, the Uni­ver­si­ty of Michi­gan, Kur­ma Part­ners and PMV.

Chris Mirabel­li

Now, the team is head­ed by CEO Mike Gar­rett and CSO Rob MacLeod, with Io­n­is co-founder Chris Mirabel­li cur­rent­ly serv­ing as chair­man of the board. For Mirabel­li, who left Io­n­is way back in 1993 but was there ear­ly in the an­ti­sense move­ment, Flamin­go rep­re­sents a ma­jor break­through for ASO tech­nol­o­gy and a sign of how the field has come in the past few decades.

“It re­al­ly is a rich area for drug dis­cov­ery and par­tic­u­lar­ly on­col­o­gy,” Mirabel­li told End­points News. “When I got rein­tro­duced to take a look at this par­tic­u­lar com­pa­ny, it was this sort of in­tro­duc­tion to lncR­NAs and my re-in­tro­duc­tion to have far the field had come with oligonu­cleotides and how much each chal­lenge had been met and knocked down. It was the abil­i­ty to get back to my roots.”

The biotech’s lead “Gen 2.5” ASOs tar­get gene tran­scrip­tion fac­tors and what are known as splice-site vari­ants, but the work gets re­al­ly in­ter­est­ing with its on­ly de­clared pre­clin­i­cal can­di­date tar­get­ing MALAT1 — an lncR­NA tar­get Flamin­go thinks could have a big ther­a­peu­tic ben­e­fit in breast can­cer and oth­er tu­mor types. The drug is a prod­uct of re­search out of David Spec­tor’s lab at Cold Spring Har­bor, the fer­tile ground from which Io­n­is and Bio­gen’s Spin­raza sprung.

The mys­te­ri­ous lncR­NA — pro­nounced “link RNA” — is a form of RNA which has a func­tion still lit­tle known to sci­ence. You may re­mem­ber it in its cir­cu­lar form as the back­bone be­hind Flag­ship start­up Laronde, which is aim­ing to de­sign pro­gram­ma­ble “eR­NA” based on the lncR­NA de­sign. But Flamin­go wants to test lncR­NA’s con­nec­tion to can­cer, a still nascent sci­en­tif­ic field but one the biotech be­lieves could of­fer a ma­jor ther­a­peu­tic break­through.

Rob MacLeod

“On­col­o­gy typ­i­cal­ly leads the cut­ting edge be­cause of ac­cess to tu­mor tis­sue and ma­te­ri­als so more is known about lncR­NA in on­col­o­gy than any oth­er ther­a­peu­tic area,” MacLeod told End­points. “More­over, with func­tion­al screens, CRISPR screens and oth­er ways to func­tion­al­ize the genome, it’s be­com­ing clear that there are dri­ver lncR­NAs im­por­tant in cer­tain ma­lig­nan­cies and sub­sets of cer­tain ma­lig­nan­cies.”

The Flamin­go team thinks that an­ti­sense oligonu­cleotides could have a ther­a­peu­tic ef­fect on lncR­NA, once thought to be an un­drug­gable tar­get. So far, the re­sults against MALAT1 are pre­clin­i­cal, but the team thinks those ear­ly da­ta could prove win­ning in hu­mans giv­en ear­ly re­sults show­ing a con­nec­tion be­tween MALAT1 ge­net­ic de­ple­tion and a “dra­mat­ic phe­no­type” in breast can­cer mod­els, MacLeod said.

“We’re go­ing ini­tial­ly in­to breast can­cer, but there are a large num­ber of op­por­tu­ni­ties for MALAT1 through­out on­col­o­gy — it’s been im­pli­cat­ed in many sol­id and hema­to­log­i­cal stud­ies,” MacLeod said. The team ex­pects a po­ten­tial Phase I to start as ear­ly as late 2022.

De­vel­op­ing even more lncR­NA-tar­get­ed drugs is the long-term goal, but the first check­point for Flamin­go will be its three clin­i­cal drugs tar­get­ing STAT-3, An­dro­gen Re­cep­tor (AR) and IRF4 — two tran­scrip­tion fac­tors and a splice-site vari­ant.

Both the STAT-3 and AR can­di­dates have turned out ear­ly hu­man da­ta, and Flamin­go sees a path for­ward in de­vel­op­ing both as per­son­al­ized med­i­cines for pre-se­lect­ed pa­tients as well as pur­su­ing an ag­gres­sive com­bi­na­tion pro­gram with oth­er drugs. In the case of the STAT-3 can­di­date, dubbed dan­vatirsen, the drug has shown some ben­e­fit when part­nered with As­traZeneca PD-1 drug Imfinzi, and the biotech is in­ter­est­ed in team­ing up with oth­er im­mune check­point in­hibitors to test ef­fi­ca­cy.

Mean­while, Flamin­go’s IRF4 can­di­date is just now en­ter­ing hu­man test­ing, and Flamin­go thinks it could be a nat­ur­al com­bo drug as can­cer meds like Revlim­id re­quire IRF4 knock­down to func­tion prop­er­ly.

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Merck CEO Rob Davis

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Alexander Lefterov/Endpoints News

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From left to right: Mark Springel, Kristina Wang, Lin Ao, Soufiane Aboulhouda

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Albert Bourla, Pfizer CEO (John Thys, Pool via AP Images)

Covid-19 roundup: Pfiz­er/BioN­Tech sub­mit vac­cine da­ta to FDA for younger chil­dren; Doc­tors kept pre­scrib­ing hy­drox­y­chloro­quine

Pfizer and BioNTech said Tuesday they submitted to FDA positive data from a Phase II/III trial of their Covid-19 vaccine in children aged 5 to less than 12 years old.

A formal EUA submission for the vaccine in these children is expected to follow “in the coming weeks,” the companies said in a statement.

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