When Flag­ship Pi­o­neer­ing propped up a small re­search team back in 2017 to study a lit­tle-known cir­cu­lar form of RNA, it wasn’t ex­act­ly a high-pro­file project. But with mR­NA pro­vid­ing the blue­print, that nascent biotech thinks it may have found the gold­mine of all gold­mines — and it’s all found­ed on a quixot­ic lit­tle mol­e­cule dubbed “eR­NA.”

Diego Mi­ralles

Laronde, found­ed on sci­ence from Flag­ship gen­er­al part­ner Avak Kahve­jian and led by CEO-part­ner and for­mer Vi­vid­ion chief Diego Mi­ralles, thinks eR­NA could be the fu­ture of drug­mak­ing, aug­ment­ing or re­plac­ing al­to­geth­er stan­dard drugs. On Mon­day, the biotech for­mal­ly launched with a $50 mil­lion check from Flag­ship and some huge am­bi­tions de­spite its rel­a­tive­ly mea­ger pock­et­book.

Hear this: By 2031, Laronde be­lieves it can de­vel­op and mar­ket 100 prod­ucts for use across a broad range of dis­eases, ef­fec­tive­ly re­plac­ing the small mol­e­cule-bi­o­log­ics di­ad that has dom­i­nat­ed drug de­vel­op­ment for decades. That’s right — 100.

The sto­ry of how eR­NA came to be starts with a cir­cu­lar, mys­te­ri­ous class of nat­u­ral­ly oc­cur­ring RNA dubbed lncR­NA, or long non-cod­ing RNA. Re­searchers iden­ti­fied the class decades ago, not­ing that un­like mR­NA, lncR­NA doesn’t in­ter­act with ri­bo­somes or code for pro­teins. They do have some ef­fect on epi­ge­net­ic con­trol, swim­ming around in both the cy­to­plasm and nu­cle­us, but that func­tion is still not to­tal­ly clear.

What cap­tured re­searchers’ in­ter­est was their shape: lncR­NA forms in a ring and folds for dif­fer­ent func­tions. That shape al­lows them to es­cape en­zymes prowl­ing in the cy­to­plasm and last much longer than mR­NA. In 2017, un­der the lead­er­ship of Kahve­jian, a for­mer found­ing CEO at Ring Ther­a­peu­tics and Ru­bius Ther­a­peu­tics, Laronde’s small “ex­plo­ration” re­search team was kick­start­ed to in­ves­ti­gate the role of lncR­NA in the cell and pos­si­ble ther­a­peu­tic ap­pli­ca­tions.

At the same time, as you’ll know, an­oth­er Flag­ship start­up, Mod­er­na, was busy at work in­ves­ti­gat­ing mR­NA. The func­tion of mR­NA as a ther­a­peu­tic was fair­ly ob­vi­ous — if you could teach a hu­man cell to pro­duce an­ti­bod­ies, pro­teins, pep­tides and chan­nels/re­cep­tors then you could the­o­ret­i­cal­ly solve most dis­eases — but mR­NA are one-hit­ter quit­ters in terms of tran­scrip­tion and don’t hang around the cell af­ter they’re tran­scribed.

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That’s when Kahve­jian’s team had a break­through: What if you could com­bine the best of both worlds from mR­NA and lncR­NA? By jam­ming what’s called an “in­ter­nal ri­bo­some en­try site” — the same mech­a­nism virus­es use to hi­jack ri­bo­somes — on­to an lncR­NA, Laronde’s re­searchers could make those non-cod­ing rings trans­lat­able in much the same way as mR­NA. From that eu­re­ka mo­ment came eR­NA — “e” for “end­less.”

Un­like mR­NA, which can on­ly pro­duce pro­teins that last days, Laronde thinks its in vi­vo man­u­fac­tur­ing ma­chines can pro­duce the same pro­teins for weeks to months with­out trip­ping the in­nate im­mune sys­tem or ex­onu­cle­ase en­zymes over time.

“We see this as a new class of med­i­cines, not just a sin­gle biotech com­pa­ny with a hand­ful of prod­ucts,” Kahve­jian said. “We are very con­vinced that by virtue of hav­ing these prop­er­ties of per­sis­tent pro­tein ex­pres­sion and the abil­i­ty to make any pro­tein in or on cells and in­side the body, we can ad­dress a re­al­ly broad range of things for a whole set of dif­fer­ent kinds of pro­teins and many dis­eases.”

In terms of how the biotech will get to 100? That’s a lit­tle com­pli­cat­ed.

First, Laronde’s eR­NA plat­form is pro­gram­ma­ble, they say, al­low­ing the biotech to tweak what it calls “pro­tein-cod­ing cas­settes” to pro­duce dif­fer­ent com­plex mol­e­cules in vi­vo. That plug-and-play de­sign, Laronde said, great­ly re­duces the work­load in dis­cov­ery and de­vel­op­ment. In­stead of hunt­ing rare dis­eases right away, Laronde is go­ing af­ter bi­ol­o­gy it says is al­ready high­ly val­i­dat­ed, which could go a long way to tak­ing a big bite out of the 100-drug bench­mark.

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Then there’s the “Gi­ga­base Fac­to­ry” that Laronde aims to build, which us­es a mod­u­lar, pod-based ap­proach for man­u­fac­tur­ing to max­i­mize scale with the small­est pos­si­ble foot­print. The name bor­rows from the Tes­la play­book — in fact, Mi­ralles men­tions Tes­la mul­ti­ple times on our call — which serves as a help­ful win­dow in­to the Laronde team’s psy­chic in­flu­ence.

Laronde will be the first ten­ant at a new Flag­ship lease in Somerville, MA, for its ever ex­pand­ing plat­form, Mi­ralles said, and will es­tab­lish man­u­fac­tur­ing space there for its first clin­i­cal stud­ies.

Man­u­fac­tur­ing will present a key chal­lenge as Laronde gears up for hu­man tri­als and be­yond, and it’s al­ready brought on its first man­u­fac­tur­ing head be­fore launch, Mi­ralles said. But the rapid pro­duc­tion of the mR­NA vac­cines has proven that bil­lions of dos­es of mR­NA can be man­u­fac­tured in a short time­frame with­out the stan­dard scale-up needs.

“We’re sit­ting on the shoul­ders of gi­ants in the mR­NA field,” Mi­ralles said. “In the last 18 months, we’ve gone from mR­NA al­most as an idea to dos­ing hun­dreds of mil­lions of peo­ple. That has proven that pro­gram­ma­ble RNA plat­forms have changed the game in terms of time­lines to bring these drugs to mar­kets and changed the game in terms of scale.”

But here’s the thing: Flag­ship is foot­ing just $50 mil­lion in launch mon­ey to get Laronde off the ground, which will put a huge onus on the fledg­ling firm to bird dog in­vestors to fund its fac­to­ry scheme as it grows and help hire the 200 em­ploy­ees it wants to bring on board with­in the first two years. For any oth­er biotech, hir­ing 200 em­ploy­ees from scratch in 48 months would be enough of a lo­gis­ti­cal night­mare to make your head spin.

At the root of these huge plans is one thing: be­lief. Be­lief in the tech, be­lief in the mag­ic sauce dri­ving Flag­ship’s brain trust and be­lief there’s a bet­ter way to do ther­a­peu­tics. If the Laronde team is right, the pay­off could dis­rupt an in­dus­try worth hun­dreds of bil­lions of dol­lars and moot decades worth of R&D in an­ti­bod­ies and small mol­e­cules that Mi­ralles said don’t work well for pa­tients and are dif­fi­cult and ex­pen­sive to ac­cess.

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“We need to think dif­fer­ent­ly about what these pro­gram­ma­ble plat­forms can do,” Mi­ralles said. “This is a com­plete­ly new class of med­i­cines that can do things we could nev­er do be­fore.”

As for the im­mense amount of clin­i­cal work that would have to go in to bring­ing 100 prod­ucts to mar­ket in a decade? Laronde is open to con­sid­er­ing its op­tions in terms of how best to bring each of its prod­ucts in­to the clin­ic — whether that’s so­lo, through part­ner­ships, fu­ture spin­outs or sales. Mi­ralles, a quick talk­er with the charis­ma of a big-tent preach­er, likens the biotech’s po­ten­tial to the late 19th cen­tu­ry oil boom: Start drilling, no mat­ter where you are, and you may find black gold.

But the whop­ping size of a po­ten­tial clin­i­cal pro­gram isn’t all that im­por­tant when you con­sid­er the trans­lata­bil­i­ty of eR­NA, Mi­ralles says. Prov­ing eR­NA works in one eu­kary­ot­ic cell should mean ef­fi­ca­cy across eu­kary­ot­ic cells, he said, a big dif­fer­en­ti­at­ing fac­tor from tra­di­tion­al ther­a­peu­tics. If you can cut risk out of the clin­ic, he says, you can spur a ma­jor break­through in the fail­ure-rid­den and lengthy de­vel­op­ment process.

“There are days that I wake up and I’m like, ‘whoa, we could do this,’” Mi­ralles said. “It’s such a game-chang­er — tru­ly, this is a game-chang­er — that in or­der to un­der­stand all the in­fi­nite im­pli­ca­tions of the plat­form, it re­al­ly takes a while to ad­just to think dif­fer­ent­ly.”



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