Ram Aiyar, Korro CEO

Can RNA edit­ing take At­las start­up where Ver­tex could­n't go? Ko­r­ro lands $116M to find out

As the CEO of RNA edit­ing start­up Ko­r­ro Bio, Ram Ai­yar of­ten gets the same ques­tion.

“I get al­ways asked, you know, if you can fix DNA, why both­er with RNA?” he told End­points News. “And it’s like ask­ing, which child do you pre­fer — your old­er one or your younger one?”

But in­vestors are ap­pre­ci­at­ing the dif­fer­ence. More than a year af­ter clos­ing its Se­ries A just shy of the megaround mark, Ko­r­ro Bio is back in the spot­light with $116 mil­lion in fresh cash and a lead can­di­date — tar­get­ing al­pha-1 an­tit­rypsin de­fi­cien­cy, or AATD.

Where­as gene edit­ing on the DNA lev­el promis­es a one-and-done ap­proach to ge­net­ic dis­or­ders com­pared to the tra­di­tion­al ap­proach of block­ing prob­lem­at­ic pro­teins, RNA edit­ing oc­cu­pies a space some­where in be­tween: a tran­sient yet pre­cise fix that gets to the root of a dis­ease.

And un­like the oth­er RNA modal­i­ties, from an­ti­sense oligonu­cleotides to RNA in­ter­fer­ence, Ko­r­ro is not in­ter­est­ed in knock­ing down pro­duc­tion of path­o­gen­ic pro­teins.

Nes­san Berming­ham

In­spired by a nat­ur­al mech­a­nism in squid and oc­to­pus, the biotech’s sci­en­tists use oligonu­cleotide guides to re­cruit an en­doge­nous en­zyme known as ADAR to a spe­cif­ic RNA site where they want to con­vert an A to a G — the kind of change that can make a world of dif­fer­ence for dis­or­ders like Rett syn­drome, co-founder and chair­man Nes­san Berming­ham pre­vi­ous­ly not­ed.

“All the tar­gets that we look at, we’re look­ing at it from a gain of func­tion stand­point,” Ai­yar said. “So ei­ther in­creas­ing the half life of a pro­tein, or up­reg­u­lat­ing the pro­tein, or re­pair­ing the pro­tein that is at a low lev­el, is re­al­ly go­ing to be the fo­cus. It’s a modal­i­ty that on­ly small mol­e­cules cur­rent­ly re­al­ly play in, but they haven’t been able to do that suc­cess­ful­ly be­cause they’re not high­ly spe­cif­ic.”

Ai­yar be­lieves those unique char­ac­ter­is­tics would al­low Ko­r­ro to tar­get preva­lent in­di­ca­tions, set­ting them apart from peers like Shape Ther­a­peu­tics, which he notes is fo­cus­ing on per­ma­nent edit­ing. And AATD, with some­where be­tween 100,000 and 150,000 pa­tients, is just one of them.

First brought on­to the broad­er biotech stage by Ver­tex, AATD is marked by mis­fold­ed pro­teins that go from the liv­er to the lung. Ver­tex tried to fix it by bind­ing to the pro­tein in a way that it be­lieves is re­spon­si­ble for the mis­fold­ing, but culled its ini­tial small mol­e­cule can­di­dates af­ter de­cid­ing they’re un­like­ly to show clin­i­cal ben­e­fit.

“It’s a very, very dif­fer­en­ti­at­ed pro­gram rel­a­tive to small mol­e­cule cor­rec­tors be­cause they’re just sit­ting in the pock­et and try­ing to pre­vent the mis­fold­ing, where­as we are fix­ing the amino acid se­quence on the RNA side to en­sure prop­er fold­ing,” Ai­yar said.

De­liv­ery, he reck­ons, will be the main chal­lenge here. But since Ko­r­ro is work­ing with mech­a­nisms like GalNAc and LNPs, Ai­yar notes that “we are stand­ing on shoul­ders of gi­ants” like Al­ny­lam and Io­n­is.

Even­tide As­set Man­age­ment led the Se­ries B, with par­tic­i­pa­tion from new in­vestors Fi­deli­ty Man­age­ment & Re­search Com­pa­ny, In­vus, Point72, Veri­tion Fund Man­age­ment, Monashee In­vest­ment Man­age­ment, Six­ty De­gree Cap­i­tal and an ad­di­tion­al health­care spe­cial­ist fund. All ex­ist­ing in­vestors joined, bring­ing to the syn­di­cate At­las Ven­ture, NEA, Wu Cap­i­tal, Qim­ing Ven­ture Part­ners USA, Sur­vey­or Cap­i­tal (a Citadel com­pa­ny), Cor­morant As­set Man­age­ment, MP Health­care Ven­ture Man­age­ment and Alexan­dria Ven­ture In­vest­ments.

Hav­ing grown the team from 27 to 59 in just around eight months, Ai­yar ex­pects the fund­ing to fu­el a con­tin­ued hir­ing dri­ve so Ko­r­ro has enough staffers to con­struct a siz­able pipeline. They’re de­vel­op­ing a CNS pro­gram to bal­ance out the lead liv­er in­di­ca­tion, with oth­er chron­ic in­di­ca­tions in mind, be­fore get­ting in­to the clin­ic, ide­al­ly in the next 18 months.

“The bi­ol­o­gy here is very nov­el,” he said. “I think it’s go­ing to be hard for peo­ple to dab­ble rather than, you know, take a very con­cert­ed ef­fort in terms of clin­i­cal de­vel­op­ment, be­cause the last thing you want to do is get to the clin­ic with a com­pound that looks good and then fall off the cliff very fast.”

ZS Per­spec­tive: 3 Pre­dic­tions on the Fu­ture of Cell & Gene Ther­a­pies

The field of cell and gene therapies (C&GTs) has seen a renaissance, with first generation commercial therapies such as Kymriah, Yescarta, and Luxturna laying the groundwork for an incoming wave of potentially transformative C&GTs that aim to address diverse disease areas. With this renaissance comes several potential opportunities, of which we discuss three predictions below.

Allogenic Natural Killer (NK) Cells have the potential to displace current Cell Therapies in oncology if proven durable.

Despite being early in development, Allogenic NKs are proving to be an attractive new treatment paradigm in oncology. The question of durability of response with allogenic therapies is still an unknown. Fate Therapeutics’ recent phase 1 data for FT516 showed relatively quicker relapses vs already approved autologous CAR-Ts. However, other manufacturers, like Allogene for their allogenic CAR-T therapy ALLO-501A, are exploring novel lymphodepletion approaches to improve persistence of allogenic cells. Nevertheless, allogenic NKs demonstrate a strong value proposition relative to their T cell counterparts due to comparable response rates (so far) combined with the added advantage of a significantly safer AE profile. Specifically, little to no risk of graft versus host disease (GvHD), cytotoxic release syndrome (CRS), and neurotoxicity (NT) have been seen so far with allogenic NK cells (Fig. 1). In addition, being able to harness an allogenic cell source gives way to operational advantages as “off-the-shelf” products provide improved turnaround time (TAT), scalability, and potentially reduced cost. NKs are currently in development for a variety of overlapping hematological indications with chimeric antigen receptor T cells (CAR-Ts) today, and the question remains to what extent they will disrupt the current cell therapy landscape. Click for more details.

Lat­est news on Pfiz­er's $3B+ JAK1 win; Pacts over M&A at #JPM22; 2021 by the num­bers; Bio­gen's Aduhelm reck­on­ing; The sto­ry of sotro­vimab; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

For those of you who attended #JPM22 in any shape or form, we hope you had a fruitful time. Regardless of how you spent the past hectic week, may your weekend be just what you need it to be.

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A $3B+ peak sales win? Pfiz­er thinks so, as FDA of­fers a tardy green light to its JAK1 drug abroc­i­tinib

Back in the fall of 2020, newly crowned Pfizer chief Albert Bourla confidently put their JAK1 inhibitor abrocitinib at the top of the list of blockbuster drugs in the late-stage pipeline with a $3 billion-plus peak sales estimate.

Since then it’s been subjected to serious criticism for the safety warnings associated with the class, held back by a cautious FDA and questioned when researchers rolled out a top-line boast that their heavyweight contender had beaten the champ in the field of atopic dermatitis — Dupixent — in a head-to-head study.

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Robert Califf, FDA commissioner nominee (Graeme Sloan/Sipa USA/Sipa via AP Images)

Rob Califf ad­vances as Biden's FDA nom­i­nee, with a close com­mit­tee vote

Rob Califf’s second confirmation process as FDA commissioner is already much more difficult than his near unanimous confirmation under the Obama administration.

The Senate Health Committee on Thursday voted 13-8 in favor of advancing Califf’s nomination to a full Senate vote. Several Democrats voted against Califf, including Sen. Bernie Sanders and Sen. Maggie Hassan. Several other Democrats who aren’t on the committee, like West Virginia’s Joe Manchin and Ed Markey of Massachusetts, also said Thursday that they would not vote for Califf. Markey, Hassan and Manchin all previously expressed reservations about the prospect of Janet Woodcock as an FDA commissioner nominee too.

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Michel Vounatsos, Biogen CEO (World Economic Forum/Ciaran McCrickard)

Bio­gen vows to fight CM­S' draft cov­er­age de­ci­sion for Aduhelm be­fore April fi­nal­iza­tion

Biogen executives made clear in an investor call Thursday they are not preparing to run a new CMS-approved clinical trial for their controversial Alzheimer’s drug anytime soon.

As requested in a draft national coverage decision from CMS earlier this week, Biogen and other anti-amyloid drugs will need to show “a meaningful improvement in health outcomes” for Alzheimer’s patients in a randomized, placebo-controlled trial to get paid for their drugs, rather than just the reduction in amyloid plaques that won Aduhelm its accelerated approval in June.

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CRO own­er pleads guilty to ob­struct­ing FDA in­ves­ti­ga­tion in­to fal­si­fied clin­i­cal tri­al da­ta

The co-owner of a Florida-based clinical research site pleaded guilty to lying to an FDA investigator during a 2017 inspection, revealing that she falsely portrayed part of a GlaxoSmithKline pediatric asthma study as legitimate, when in fact she knew that certain data had been falsified, the Department of Justice said Wednesday.

Three other employees — Yvelice Villaman Bencosme, Lisett Raventos and Maytee Lledo — previously pleaded guilty and were sentenced in connection with falsifying data associated with the trial at the CRO Unlimited Medical Research.

Susan Galbraith, AstraZeneca EVP, Oncology R&D

Can­cer pow­er­house As­traZeneca rolls the dice on a $75M cash bet on a buzzy up­start in the on­col­o­gy field

After establishing itself in the front ranks of cancer drug developers and marketers, AstraZeneca is putting its scientific shoulder — and a significant amount of cash — behind the wheel of a brash new upstart in the biotech world.

The pharma giant trumpeted news this morning that it is handing over $75 million upfront to ally itself with Scorpion Therapeutics, one of those biotechs that was newly birthed by some top scientific, venture and executive talent and bequeathed with a fortune by way of a bankroll to advance an only hazily explained drug platform. And they are still very much in the discovery and preclinical phase.

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‘Skin­ny la­bels’ on gener­ics can save pa­tients mon­ey, re­search shows, but re­cent court de­ci­sions cloud fu­ture

New research shows how generic drug companies can successfully market a limited number of approved indications for a brand name drug, prior to coming to market for all of the indications. But several recent court decisions have created a layer of uncertainty around these so-called “skinny” labels.

While courts have generally allowed generic manufacturers to use their statutorily permitted skinny-label approvals, last summer, a federal circuit court found that Teva Pharmaceuticals was liable for inducing prescribers and patients to infringe GlaxoSmithKline’s patents through advertising and marketing practices that suggested Teva’s generic, with its skinny label, could be employed for the patented uses.

A patient in Alaska receiving an antibody infusion to prevent Covid hospitalizations in September. All but one of these treatments has been rendered useless by Omicron (Rick Bowmer/AP Images)

How a tiny Swiss lab and two old blood sam­ples cre­at­ed one of the on­ly ef­fec­tive drugs against Omi­cron (and why we have so lit­tle of it)

Exactly a decade before a novel coronavirus broke out in Wuhan, Davide Corti — a newly-minted immunologist with frameless glasses and a quick laugh — walked into a cramped lab on the top floor of an office building two hours outside Zurich. He had only enough money for two technicians and the ceiling was so low in parts that short stature was a job requirement, but Corti believed it’d be enough to test an idea he thought could change medicine.

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