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.

Biogen CEO Michel Vounatsos (via Getty Images)

With ad­u­canum­ab caught on a cliff, Bio­gen’s Michel Vounatsos bets bil­lions on an­oth­er high-risk neu­ro play

With its FDA pitch on the Alzheimer’s drug aducanumab hanging perilously close to disaster, Biogen is rolling the dice on a $3.1 billion deal that brings in commercial rights to one of the other spotlight neuro drugs in late-stage development — after it already failed its first Phase III.

The big biotech has turned to Sage Therapeutics for its latest deal, close to a year after the crushing failure of Sage-217, now dubbed zuranolone, in the MOUNTAIN study.

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Pascal Soriot (AP Images)

UP­DAT­ED: As­traZeneca, Ox­ford on the de­fen­sive as skep­tics dis­miss 70% av­er­age ef­fi­ca­cy for Covid-19 vac­cine

On the third straight Monday that the world wakes up to positive vaccine news, AstraZeneca and Oxford are declaring a new Phase III milestone in the fight against the pandemic. Not everyone is convinced they will play a big part, though.

With an average efficacy of 70%, the headline number struck analysts as less impressive than the 95% and 94.5% protection that Pfizer/BioNTech and Moderna have boasted in the past two weeks, respectively. But the British partners say they have several other bright spots going for their candidate. One of the two dosing regimens tested in Phase III showed a better profile, bringing efficacy up to 90%; the adenovirus vector-based vaccine requires minimal refrigeration, which may mean easier distribution; and AstraZeneca has pledged to sell it at a fraction of the price that the other two vaccine developers are charging.

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Covid-19 roundup: Eu­rope pur­chas­es 80M dos­es of Mod­er­na's vac­cine; CO­V­AXX se­cures $2.8B in emerg­ing mar­ket pre-or­ders

With the announcement of its vaccine efficacy data last week, Moderna is starting to line up customers for its Covid-19 mRNA jabs.

The Massachusetts-based biotech announced Wednesday it has agreed to sell an initial round of 80 million doses to the European Commission, with the option to double the amount to 160 million. Once the member states rubber stamp the approval, the deal will be finalized.

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Bob Nelsen (Photo by Michael Kovac/Getty Images)

Bob Nelsen rais­es $800M and re­cruits a star-stud­ded board to build the 'Fox­con­n' of biotech

Bob Nelsen spent his pandemic spring in his Seattle home, talking on the phone with Luciana Borio, the scientist who used to run pandemic preparedness on the National Security Council, and fuming with her about the dire state of American manufacturing.

Companies were rushing to develop vaccines and antibodies for the new virus, but even if they succeeded, there was no immediate supply chain or infrastructure to mass-produce them in a way that could make a dent in the outbreak.

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Feng Tian, Ambrx CEO (Ambrx)

Af­ter 5 qui­et years, a for­mer Scripps spin­out rais­es $200M and an­nounces plans to try again at an IPO

The first time San Diego biotech Ambrx tried to go public in 2014, they failed and the company’s board switched to a radically different strategy: They sold themselves for an undisclosed amount to a syndicate of Chinese investors and pharma companies.

Now, after 5 quiet years, that syndicate has raised a mountain of cash and indicated they’ll soon make another bid to go public.

Earlier this month, Ambrx raised $200 million in what they billed as a crossover round financed by Fidelity, BlackRock, Cormorant Asset Management, HBM Healthcare Investments, Invus, Adage Capital Partners and Suvretta Capital Management. It’s the largest amount they’ve ever raised and, according to Crunchbase figures, more than doubles the total amount of VC capital collected since their launch 17 years ago.

Jason Kelly, Ginkgo Bioworks CEO (Kyle Grillot/Bloomberg via Getty Images)

Af­ter Ko­dak de­ba­cle, US lends $1.1B to a syn­thet­ic bi­ol­o­gy com­pa­ny and their big Covid-19, mR­NA plans

In mid-August, as Kodak’s $765 million government-backed push into drug manufacturing slowly fell apart in national headlines, Ginkgo Bioworks CEO Jason Kelly got a message from his company’s government liaison: HHS wanted to know if they, too, might want a loan.

The government’s decision to lend Kodak three quarters of a billion dollars raised eyebrows because Kodak had never made drugs before. But Ginkgo, while not a manufacturing company, had spent the last decade refining new ways to produce materials inside cells and building automated facilities across Boston.

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Michelle Longmire, Medable CEO (Jeff Rumans)

Med­able gets $91M for vir­tu­al clin­i­cal tri­als, bring­ing to­tal raise to $136M

As biotechs look to get clinical studies back on track amid the pandemic, Medable returned to the venture well for the second time this year, bagging a $91 million Series C to build out its virtual trial platform.

The software provider recently launched three new apps for decentralizing clinical trials, and saw a 500% revenue spike this year. And it isn’t alone. Back in August, Science 37 secured a $40 million round for its virtual trial tech, with support from Novartis, Sanofi Ventures and Amgen. Patients and researchers are taking a liking to the online approach, suggesting regulators could allow it to become a new normal even after the pandemic is over.

The ad­u­canum­ab co­nun­drum: The PhI­II failed a clear reg­u­la­to­ry stan­dard, but no one is cer­tain what that means any­more at the FDA

Eighteen days ago, virtually all of the outside experts on an FDA adcomm got together to mug the agency’s Billy Dunn and the Biogen team when they presented their upbeat assessment on aducanumab. But here we are, more than 2 weeks later, and the ongoing debate over that Alzheimer’s drug’s fate continues unabated.

Instead of simply ruling out any chance of an approval, the logical conclusion based on what we heard during that session, a series of questionable approvals that preceded the controversy over the agency’s recent EUA decisions has come back to haunt the FDA, where the power of precedent is leaving an opening some experts believe can still be exploited by the big biotech.

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John Maraganore, Alnylam CEO (Scott Eisen/Bloomberg via Getty Images)

UP­DAT­ED: Al­ny­lam gets the green light from the FDA for drug #3 — and CEO John Maraganore is ready to roll

Score another early win at the FDA for Alnylam.

The FDA put out word today that the agency has approved its third drug, lumasiran, for primary hyperoxaluria type 1, better known as PH1. The news comes just 4 days after the European Commission took the lead in offering a green light.

An ultra rare genetic condition, Alnylam CEO John Maraganore says there are only some 1,000 to 1,700 patients in the US and Europe at any particular point. The patients, mostly kids, suffer from an overproduction of oxalate in the liver that spurs the development of kidney stones, right through to end stage kidney disease.

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