Nello Mainolfi via YouTube

At­las-backed Kymera grabs $102M as its pro­tein degra­da­tion tech­nol­o­gy heads in­to clin­ic

When Bruce Booth and Nel­lo Main­olfi start­ed plan­ning a pro­tein degra­da­tion com­pa­ny, the field was open and sparse, dot­ted with a cou­ple of hope­ful star­tups and larg­er play­ers mak­ing ex­plorato­ry for­ays. Booth called it a “broad new modal­i­ty with plen­ty of free­dom to op­er­ate across po­ten­tial­ly every ther­a­peu­tic area and dis­ease state.”

Four years lat­er, Kymera Ther­a­peu­tics is look­ing to be­come one of the first of what will like­ly be many pro­tein degra­da­tion com­pa­nies to en­ter the clin­ic. The com­pa­ny an­nounced $102 mil­lion in Se­ries C fund­ing and a plan to bring its lead drug tar­get­ing IRAK4 in­to the first tri­als by next year. Biotech­nol­o­gy Val­ue Fund and Red­mile Group led the round.

“We are at the cusp of tran­si­tion­ing from a re­search to a de­vel­op­ment or­ga­ni­za­tion — or, I should say, to a re­search and de­vel­op­ment or­ga­ni­za­tion,” Main­olfi, now the CEO, told End­points News.  “This fi­nanc­ing re­al­ly al­lows to build to­ward the con­cept of build­ing a ful­ly in­te­grat­ed biotech com­pa­ny around pro­tein degra­da­tion, which I think is prob­a­bly one of the most trans­for­ma­tive modal­i­ties.”

As of to­day, Kymera would like­ly be the sec­ond biotech to bring a pro­tein de­grad­er in­to the clin­ic. A year ago, Arv­inas – whose founder Craig Crews pub­lished some of the first work show­ing how pro­tein degra­da­tion could be drugged — brought what it be­lieves to be the first pro­tein de­grad­er in­to hu­man test­ing, an an­dro­gen re­cep­tor-tar­get­ing drug for prostate can­cer. C4 Ther­a­peu­tics, the oth­er ma­jor start­up that ex­ist­ed when Kymera launched, has part­ner­ships with Bio­gen, Roche, and Dana-Far­ber, but no ther­a­pies in the clin­ic.

The pro­tein is a ki­nase im­pli­cat­ed in sev­er­al can­cers. Small mol­e­cules can in­hib­it IRAK4’s prop­er­ties as a ki­nase, but the pro­tein al­so func­tions as a scaf­fold­ing pro­tein that helps build the my­d­do­some pro­tein com­plex. The com­plex is sup­posed to be ac­ti­vat­ed to re­spond to in­fec­tion but can some­times ac­ti­vate aber­rant­ly, lead­ing to in­flam­ma­to­ry or au­toim­mune dis­ease.

The idea be­hind pro­tein degra­da­tion is that in­stead of send­ing a mol­e­cule to block the pro­tein’s ki­nase bind­ing site — and leav­ing the rest of the pro­tein in­tact and func­tion­ing — re­searchers can re­move the pro­tein en­tire­ly. They do this by hi­jack­ing the body’s in­ter­nal sys­tem to re­move pro­teins that are mis­fold­ed or are in over­abun­dance. En­zymes called E3 lig­as­es tag un­want­ed pro­teins with a pro­tein called ubiq­ui­tin, like a gen­er­al pick­ing tar­gets for an air raid. Those tagged pro­teins are then tar­get­ed by pro­teas­es and un­fold­ed in the body’s mul­ti-step garbage dis­pos­al sys­tem.

Kymera us­es small mol­e­cules to drag E3 lig­as­es to the pro­tein it wants to elim­i­nate. Their pre­clin­i­cal re­search sug­gests re­mov­ing IRAK4 in this way will help treat a rare in­flam­ma­to­ry skin con­di­tion called hidradeni­tis sup­pu­ra­ti­va and B-cell lym­phomas, among oth­er dis­eases. They al­so have pro­grams tar­get­ing the tran­scrip­tion fac­tor STAT3, which is part of the JAK path­way.

Main­olfi said the gen­er­al con­cept had been ap­par­ent for years, but ad­vance­ments around 2016 made it look fea­si­ble.

“This is tech­nol­o­gy that has fas­ci­nat­ed me for years, but what was lack­ing were re­al­ly the chem­i­cal tools,” Main­olfi said.

Since then, Kymera has built up a plat­form they say dif­fer­en­ti­ates them from some of their com­peti­tors by us­ing in­for­mat­ics to iden­ti­fy new E3 lig­as­es and the best drugs in im­munol­o­gy and on­col­o­gy. And last year they signed a $70 mil­lion col­lab­o­ra­tion with Ver­tex. Main­olfi, who stepped in­to the CEO job in No­vem­ber af­ter Lau­rent Au­doly’s de­par­ture, said it helps them ap­ply their tech­nol­o­gy in in­di­ca­tions be­yond the two they’ve fo­cused on to date.

Even­tu­al­ly, he said, pro­tein degra­da­tion is go­ing to be every­where.

“When I look at pro­tein degra­da­tion, I look at a field just like an­ti­body or RNA ther­a­peu­tics 20 years ago,” Main­olfi said. “It is a field that will trans­form med­i­cine.”

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