Tuyen Ong and Avak Kahvejian

One Ring to rule them all? Flag­ship’s big bet on dom­i­nat­ing gene ther­a­py 2.0 at­tracts a $117M megaround

Over the last 18 months or so, gene ther­a­py has come in for its come­up­pance.

Long known for once-and-done boast­ing, stak­ing claims for cu­ra­tive re­sults on some of the most bit­ter dis­eases known to man, the field has been stag­gered by fail­ure, ev­i­dence of wan­ing ef­fects and fears that ef­fi­ca­cy could wick­er and flame out. And giv­en the ther­a­pies’ vi­ral con­structs, they could on­ly be giv­en once.

As a re­sult, var­i­ous com­pa­nies have been work­ing on dif­fer­ent so­lu­tions. But at Flag­ship, which has been re­think­ing what think­ing big is, there’s one still quite stealthy ef­fort that aims to sweep aside the first gen­er­a­tion of ther­a­pies and sup­plant it with some­thing com­plete­ly new.

The biotech is Ring Ther­a­peu­tics, or­ga­nized around a cen­tral big plat­form idea: that a new kind of virus they’ve found — anellovirus­es — that typ­i­cal­ly live in har­mo­ny with your im­mune sys­tem, can be used in a va­ri­ety of tis­sues for a va­ri­ety of ther­a­peu­tic pur­pos­es. And, they hope, anellovirus­es can sim­ply re­place the still prob­lem­at­ic ade­n­ovirus­es that dom­i­nat­ed the first wave in this race, of­fer­ing a new fleet choice that can per­ma­nent­ly al­ter the field.

Like oth­er Flag­ship mod­els, the plat­form play here is based on lengthy lab work. Ring has been in busi­ness since 2017. And you don’t see any­one sweat­ing the fact that they’re on a hard march to their 5th an­niver­sary with no plans to be in the clin­ic any­time this year. At least, nei­ther the CEO-part­ner in­volved, Night­star vet­er­an Tuyen Ong, or Flag­ship’s Avak Kahve­jian sound con­cerned.

For them, this is a shot at the first true dis­rup­tion in gene ther­a­py in 50 years. They’re out to make biotech his­to­ry. Here’s the Flag­ship found­ing part­ner, Kahve­jian:

You know that Flag­ship doesn’t nec­es­sar­i­ly want to rush in­to the clin­ic with one pro­gram. We re­al­ly, tru­ly see this as a mul­ti­modal­i­ty, mul­ti­prod­uct plat­form. And as such, we want to stag­ger a num­ber of clin­i­cal en­tries to­geth­er with­in a rea­son­able time­frame where they’re over­lap­ping with each oth­er. So all of those pre­clin­i­cal stud­ies have to line up. And we want to demon­strate some of these re­al­ly in­ter­est­ing val­ue propo­si­tions. And pick­ing the right way to do that is go­ing to be im­por­tant.

There’s a pub­li­ca­tion com­ing soon that Kahve­jian is ex­cit­ed about. And Ong sounds hap­py to be in this spot, as they move in­to the IND stage.

I know you hear this prob­a­bly from a num­ber of dif­fer­ent biotechs, but I of­ten use the term, it’s a lit­tle bit corny, but it’s one Ring to rule them all. Be­cause when you look at gene ther­a­py, dif­fer­ent com­pa­nies are in­no­vat­ing on dif­fer­ent fronts. So there’s the cap­sid evo­lu­tion as you talked about, cap­sid en­gi­neer­ing, man­u­fac­tur­ing and the oth­er piece, which is the pay­loads. What Ring is do­ing is ac­tu­al­ly in­no­vat­ing on mul­ti­ple fronts. So we’ve tak­en these com­men­sal virus­es that are harm­less, they de­vel­oped spe­cif­ic ad­van­tages in terms of tro­pism, re­dos­abil­i­ty, po­ten­tial­ly be­ing more tol­er­a­ble and po­tent and we’ve been able to gen­er­ate a plat­form around that…

I think the prob­lem we have right now, John, is that we have an em­bar­rass­ment of rich­es in re­gards to which dis­eases to tar­get. I think how we’re look­ing at ba­si­cal­ly ad­dress­ing the clin­i­cal in­di­ca­tions is that one, you can have in­di­ca­tions that ad­dress both greater tol­er­a­bil­i­ty, which is an is­sue with­in the gene ther­a­py space, greater po­ten­cy, the abil­i­ty to ad­dress dif­fer­ent in­di­ca­tions that are not ad­dressed be­cause of lack of tro­pism. And then the fi­nal holy grail is to ad­dress the re­dos­abil­i­ty piece.

Ong had a front-row seat on just how ex­cit­ing, and fre­quent­ly dis­ap­point­ing, the first round of gene ther­a­pies has gone. He was head of de­vel­op­ment at Night­star un­til Bio­gen bought them out in the sum­mer of 2019. And both of Night­star’s main pro­grams just flamed out in the clin­ic, wip­ing out more than a half-bil­lion dol­lars in val­ue on Bio­gen’s books.

Ring’s sto­ry, mean­while, has at­tract­ed a much broad­er syn­di­cate to build on the Flag­ship launch round.

In­vus, Al­ti­tude Life Sci­ence Ven­tures, Part­ners In­vest­ment, UPMC En­ter­pris­es, as well as funds and ac­counts ad­vised by T. Rowe Price As­so­ci­ates, among oth­ers, joined in along­side Flag­ship Pi­o­neer­ing. They can count this as an­oth­er high-risk, high re­ward play in the Flag­ship port­fo­lio.

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.

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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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.

‘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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