Zachary Hornby. Boundless

'A fourth rev­o­lu­tion in can­cer ther­a­pies': ARCH-backed Bound­less Bio flash­es big check, makes big­ger promis­es in de­but

It was the cel­lu­lar equiv­a­lent of open­ing your car door and find­ing an ac­tive, roar­ing en­gine in the dri­ver seat.

Paul Mis­chel

Sci­en­tists learned strands of DNA could oc­ca­sion­al­ly ap­pear out­side of its tra­di­tion­al home in the nu­cle­us in the 1970s, when they ap­peared as lit­tle, in­nocu­ous cir­cles on mi­cro­scopes; in­ex­plic­a­ble but ap­par­ent­ly in­nate. But not un­til UC San Diego’s Paul Mis­chel pub­lished his first study in Sci­ence in 2014 did re­searchers re­al­ize these cir­cles were not on­ly ac­tive but po­ten­tial­ly over­ac­tive and dri­ving some can­cer tu­mors’ su­per­hu­man growth.

That in­sight and the en­su­ing five years of re­search will now get $46 mil­lion cash and com­pa­ny in­fra­struc­ture to ramp in­to tar­get­ed ther­a­pies as Bound­less Bio emerges from stealth mode with back­ing from ARCH Ven­ture Part­ners and City Hill. Ques­tions abound, from what pre­cise­ly a drug would look like to what even gives rise to these wild DNA, but CEO Zachary Horn­by isn’t bit­ing his tongue on the po­ten­tial.

“We’re think­ing about this as a fourth rev­o­lu­tion in can­cer ther­a­pies,” Horn­by, who was most re­cent­ly COO of Igny­ta, told End­points News. The first three rev­o­lu­tions, by Horn­by’s count, are chemother­a­py in the 1940s, the first tar­get­ed ther­a­pies at the end of the 20th cen­tu­ry, and the re­cent rise of im­munother­a­py.

The road to such a rev­o­lu­tion would be long, but the em­bat­tled on­col­o­gy field may be in need of new di­rec­tion. A study re­leased in April found 97% of can­cer drugs test­ed in clin­i­cal tri­als failed to make it to mar­ket, and this month re­searchers found sys­temic tar­get­ing prob­lems plagued two decades of can­cer re­search.

The con­nec­tion be­tween this loose DNA, of­fi­cial­ly called ex­tra­chro­mo­so­mal DNA or ecD­NA, and can­cer cen­ters around a baf­fling and dead­ly fact about some tu­mors: While nor­mal cells in a high­er-or­der species like hu­mans don’t evolve with­in a gen­er­a­tion, some can­cer cells can evolve rapid­ly, en­sur­ing their sur­vival against at­tempt­ed treat­ments. Why? How? Mis­chel’s map­ping of can­cer genome points to ecD­NA.

Freed from a cell’s chro­mo­somes, the DNA can repli­cate rapid­ly. That doesn’t hurt if they code for noth­ing or some­thing be­nign, but if they code for some­thing that gives the cell an ad­van­tage, such as EGFR (a growth fac­tor), the cells will grow rapid­ly as in any clas­si­cal nat­ur­al se­lec­tion mod­el. This, Horn­by said, ap­pears in over 25% of can­cers, in­clud­ing no­to­ri­ous­ly hard to treat MET can­cers.

EGFR in­hibitors al­ready ex­ist to com­bat can­cer cells that have al­ready evolved (or been “am­pli­fied”), but Bound­less Bio plans to use Mis­chel’s in­sights to de­stroy ecD­NA in its ear­ly stages. Rather than at­tack­ing tu­mors af­ter the cells have al­ready am­pli­fied, the com­pa­ny would jam the process that gives rise to the evo­lu­tion in the first place.

“It opens a whole new av­enue of can­cer tar­gets, in­clud­ing al­low­ing us to pur­sue pa­tient pop­u­la­tions that to this point have been un­drug­gable,” Horn­by said, point­ing to MET and Myc. “That’s just a re­al­ly dif­fer­ent ap­proach than your typ­i­cal tar­get­ed ther­a­pies.”

But how they would do this is still cloudy.

Horn­by said the most promis­ing method was jam­ming the “en­zy­mat­ic ma­chin­ery” — the mol­e­c­u­lar tools and parts that al­low DNA to repli­cate and code pro­teins — as their re­search has shown the ma­chin­ery is slight­ly dif­fer­ent in ecD­NA than typ­i­cal DNA. An­oth­er method they’re ex­plor­ing is to in­hib­it the meta­bol­ic path­ways ecD­NA can use to ful­fill the de­mands caused by its high repli­ca­tion rate; in oth­er words, grow­ing DNA that are hun­gry and de­priv­ing them of food could neu­tral­ize them.

Among the most no­table things about Bound­less’ po­ten­tial ther­a­pies is that they may be ap­proved for tu­mor type, rather than can­cer type, i.e. like the new drug from Horn­by’s old com­pa­ny Igny­ta, it could treat a wide range of can­cers if the pa­tient showed ecD­NA was am­pli­fy­ing in the tu­mor.

The com­pa­ny will al­so in­vest in re­search to dis­cov­er the un­der­ly­ing mech­a­nism giv­ing rise to ecD­NA.

Has the mo­ment fi­nal­ly ar­rived for val­ue-based health­care?

RBC Capital Markets’ Healthcare Technology Analyst, Sean Dodge, spotlights a new breed of tech-enabled providers who are rapidly transforming the way clinicians deliver healthcare, and explores the key question: can this accelerating revolution overturn the US healthcare system?

Key points

Tech-enabled healthcare providers are poised to help the US transition to value, not volume, as the basis for reward.
The move to value-based care has policy momentum, but is risky and complex for clinicians.
Outsourced tech specialists are emerging to provide the required expertise, while healthcare and tech are also converging through M&A.
Value-based care remains in its early stages, but the transition is accelerating and represents a huge addressable market.

Alaa Halawaa, executive director at Mubadala’s US venture group

The ven­ture crew at Mubadala are up­ping their biotech cre­ation game, tak­ing care­ful aim at a new fron­tier in drug de­vel­op­ment

It started with a cup of coffee and a slow burning desire to go early and long in the biotech creation business.

Wrapping up a 15-year discovery stint at Genentech back in the summer of 2021, Rami Hannoush was treated to a caffeine-fueled review of the latest work UCSF’s Jim Wells had been doing on protein degradation — one of the hottest fields in drug development.

“Jim and I have known each other for the past 15 years through Genentech collaborations. We met over coffee, and he was telling me about this concept of the company that he was thinking of,” says Hannoush. “And I got immediately intrigued by it because I knew that this could open up a big space in terms of adding a new modality in drug discovery that is desperately needed in pharma.”

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Flare Therapeutics biochemists Yong Li (L) and Valerie Vivat

A $123M Flare will get Third Rock on­col­o­gy biotech in­to the clin­ic this year

Flare Therapeutics will start its first human trial this year with an investigational urothelial cancer drug after pulling together a $123 million Series B from Big Pharmas, VCs and its incubator, Third Rock Ventures.

Launched in 2021 on the idea that a biotech could finally succeed at drugging the much-sought-after but stubborn transcription factor, Flare Therapeutics said Wednesday it is now primed for the clinic after closing its large financing haul earlier this year. The raise is a relatively stark figure in a tough startup financing environment but further buoys the upbeat signals coming out of other Third Rock biotechs in recent weeks, including the $200 million CARGO Therapeutics and $100 million Rapport Therapeutics rounds.

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'Band­ing to­geth­er': 50 fe­male biotech ex­ec­u­tives lay out plans for board di­ver­si­ty, new com­pa­nies and men­tor­ing founders

Earlier this month, during the Silicon Valley Bank meltdown, Angie You recalled the speed with which female biotech CEOs were helping each other connect with bankers, get their wires through and assuage concerns during a financial implosion.

This past weekend, 50 of about 125 women who are part of that Slack group and a broader coalition self-dubbed the Biotech Sisterhood met in person in Cancun for the second rendition of an annual summit connecting female biotech CEOs. The attendance list doubled that of the inaugural gathering in Arizona 12 months ago.

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Francesco Marincola, newly-appointed Sonata Therapeutics CSO

Kite's head of re­search leaves for Flag­ship start­up Sonata

Another leader is departing Kite Pharma, and will to spend the “last part” of his career exploring how cancer evades the immune system.

Kite’s senior VP and global head of cell therapy research Francesco Marincola left the Gilead CAR-T unit last week for Sonata Therapeutics. Flagship last May unveiled the startup, which was pieced together from two fledgling biotechs Inzen and Cygnal Therapeutics. As CSO, Marincola will lead Sonata’s push to reprogram cancer cells to make them more immunogenic.

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Rohan Palekar, 89bio CEO

89bio’s PhII da­ta add to quick suc­ces­sion of NASH read­outs as field seeks turn­around

89bio said its drug was better than placebo at lessening fibrosis without worsening nonalcoholic steatohepatitis, or NASH, in two of three dose groups.

The San Francisco biotech said it thinks the Phase IIb data pave the way for a potential Phase III, following in the footsteps of another biotech in its drug class, Akero Therapeutics. To fund a late-stage study, CEO Rohan Palekar told Endpoints News 89bio “would need to raise additional capital,” with the company having about $188 million at the end of last year.

FDA in­di­cates will­ing­ness to ap­prove Bio­gen ALS drug de­spite failed PhI­II study

Ahead of Wednesday’s advisory committee hearing to discuss Biogen’s ALS drug tofersen, the FDA appeared open to approving the drug, newly released briefing documents show.

Citing the need for flexibility in a devastating disease like ALS, regulators signaled a willingness to consider greenlighting tofersen based on its effect on a certain protein associated with ALS despite a failed pivotal trial. The documents come after regulatory flexibility was part of the same rationale the agency expressed when approving an ALS drug last September from Amylyx Pharmaceuticals, indicating the FDA’s openness to approving new treatments for the disease.

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Roche and Lil­ly team up to de­vel­op blood test to de­tect ear­ly signs of Alzheimer's

Eli Lilly is teaming up with Roche to help develop a blood test to detect early signs of Alzheimer’s disease and determine whether a patient should go for further confirmatory testing.

Roche’s Elecsys Amyloid Plasma Panel (EAPP) measures pTau 181 protein assay and APOE E4 assay in human blood plasma – elevations in pTau 181 are present in the early stages of Alzheimer’s, while the presence of APO E4 is the most common genetic risk factor for the disease.

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Josep Bassaganya-Riera, NImmune Biopharma

Ex­clu­sive: Af­ter get­ting his drug back, Lan­dos founder as­sem­bles new start­up for the big PhI­II test

By the time Josep Bassaganya-Riera stepped down as founding CEO of Landos Biopharma in 2021, the company had racked up Phase II data for its top autoimmune program, completed what he called a positive end-of-Phase-II meeting with the FDA and plans to launch pivotal Phase III trials.

Since then, though, the new leaders at Landos have reshuffled their plans for the drug, omilancor, first announcing they will run a Phase IIb ahead of a Phase III and eventually shelving it altogether.

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