Nematode. Andy Murray

Com­pound nes­tled in par­a­sitic worm of­fers promise as an­tibi­ot­ic against ob­sti­nate su­per­bugs

A com­pound domi­ciled in­side the gut of a soil-dwelling par­a­sitic worm could be the chief in­gre­di­ent for a po­tent hu­man an­tibi­ot­ic de­signed to fight a class of stub­born su­per­bugs, new re­search sug­gests.

The tsuna­mi of an­tibi­ot­ic re­sis­tance is an acute glob­al threat. In the Unit­ed States, at least 2.8 mil­lion peo­ple get an an­tibi­ot­ic-re­sis­tant in­fec­tion each year, and more than 35,000 peo­ple die, ac­cord­ing to a re­cent re­port by the CDC.

The be­lea­guered field of an­tibi­otics is des­per­ate for a win­ner. For one of the biggest threats to glob­al health, the li­on’s share of an­tibi­ot­ic de­vel­op­ment is tak­ing place in a hand­ful of labs of small bio­phar­ma com­pa­nies or the halls of acad­e­mia, while big phar­ma large­ly fo­cus­es on more lu­cra­tive en­deav­ors. Mean­while, most fresh­ly ap­proved an­tibi­otics have been more po­tent ver­sions of ex­ist­ing class­es of an­tibi­otics. In short, the field is des­per­ate for fresh op­tions.

The com­pound, darobactin, is a prod­uct of Pho­torhab­dus bac­te­ria that was dis­cov­ered re­sid­ing with­in the gut of a ne­ma­tode.

Darobactin has the po­ten­tial to smoth­er Gram-neg­a­tive bac­te­ria, which cause in­fec­tions such as ty­phoid, cholera and the plague. The class of mi­crobes bran­dish­es a re­silient out­er mem­brane which as­sists them in sub­vert­ing most stan­dard an­tibi­otics. The last class of an­tibi­otics act­ing against Gram-neg­a­tive bac­te­ria was de­vel­oped in the 1960s, re­searchers not­ed in Na­ture.

Re­search on mice, con­duct­ed by a team of sci­en­tists led by Kim Lewis, pro­fes­sor of bi­ol­o­gy and di­rec­tor of the An­timi­cro­bial Dis­cov­ery Cen­ter at North­east­ern Uni­ver­si­ty, in­di­cat­ed that darobactin treat­ed E. coli and Kleb­siel­la pneu­mo­ni­ae in­fec­tions, sans any tox­i­c­i­ty.

The dis­cov­ery marks the first in­stance that the an­i­mal mi­cro­bio­me was found to har­bor an an­tibi­ot­ic that could be em­ployed in hu­mans, Lewis not­ed in a re­port pub­lished by North­east­ern ac­com­pa­ny­ing the Na­ture pub­li­ca­tion.

Ne­ma­todes and Pho­torhab­dus bac­te­ria share their din­ners, pri­mar­i­ly of the in­sect va­ri­ety. The ne­ma­tode sets its friend the Pho­torhab­dus bac­te­ria loose on say, a cater­pil­lar. The bac­te­ria ex­pels tox­ins in­to the unas­sum­ing cater­pil­lar, killing it — al­low­ing the con­niv­ing al­lies to share the spoils.

But, the Pho­torhab­dus must al­so fend off oth­er greedy din­ers — par­tic­u­lar­ly from with­in ne­ma­tode’s gut, which is typ­i­cal­ly brim­ming with the same Gram-neg­a­tive bac­te­ria that at­tack hu­mans. And be­cause the ne­ma­tode is the Pho­torhab­dus’s home, it makes sure what kills the gram-neg­a­tive pathogens doesn’t stran­gle its host.

“Since Pho­torhab­dus bac­te­ria live in the ne­ma­tode, and the ne­ma­tode is an an­i­mal just like we are, what­ev­er they make has to be non-tox­ic [for us],” Lewis said in the North­east­ern re­port.

That ad­di­tion­al ar­mor that Gram-neg­a­tive bac­te­ria en­joy is en­gi­neered by a pro­tein called Ba­mA, which acts as a guard, open­ing its gates cycli­cal­ly al­low­ing the pas­sage of fresh pro­teins to build that im­per­vi­ous pro­tec­tive shield. Darobactin makes a bee­line for Ba­mA and clogs that gate, thwart­ing the cre­ation of that cell wall and ren­der­ing the gram-neg­a­tive bac­te­ria vul­ner­a­ble to ex­ist­ing an­tibi­otics.

The re­searchers are now gun­ning to test the Ba­mA in­hibitor in hu­man tri­als.

This mech­a­nism of ac­tion po­ten­tial­ly re­solves the in­tractable prob­lem of pen­e­trat­ing the bar­ri­er of Gram-neg­a­tive bac­te­ria, they wrote in Na­ture. “There are on­ly two es­sen­tial pro­teins ex­posed on the sur­face of the out­er mem­brane – Ba­mA; and LptD17. There is lit­tle doubt that na­ture pro­duced more than one type of com­pounds act­ing against these tar­gets.”

The Na­ture ar­ti­cle in­clud­ed the con­tri­bu­tions of sci­en­tists from North­east­ern Uni­ver­si­ty, Pur­due Uni­ver­si­ty, and the J. Craig Ven­ter In­sti­tute from the Unit­ed States; Jus­tus Liebig Uni­ver­si­ty Giessen, the Ger­man Cen­ter for In­fec­tion Re­search DZIF and the Eu­ro­pean Mol­e­c­u­lar Bi­ol­o­gy Lab­o­ra­to­ry EM­BL in Ger­many; as well as the Uni­ver­si­ty of Basel in Switzer­land.

Im­age cred­it: Andy Mur­ray, A Chaos of De­light

UP­DAT­ED: Mer­ck pulls Keytru­da in SCLC af­ter ac­cel­er­at­ed nod. Is the FDA get­ting tough on drug­mak­ers that don't hit their marks?

In what could be an early shot in the battle against drugmakers that whiff on confirmatory studies to support accelerated approvals, the FDA ordered Bristol Myers Squibb late last year to give up Opdivo’s approval in SCLC. Now, Merck is next on the firing line — are we seeing the FDA buckling down on post-marketing offenders?

Merck has withdrawn its marketing approval for PD-(L)1 inhibitor Keytruda in metastatic small cell lung cancer as part of what it describes as an “industry-wide evaluation” by the FDA of drugs that do not meet the post-marketing checkpoints on which their accelerated nods were based, the company said Monday.

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Pascal Soriot, AstraZeneca CEO (AP Images)

Pas­cal So­ri­ot cash­es in As­traZeneca’s chips on Mod­er­na for $1.2B cash in­jec­tion

While still working to prove its own Covid-19 vaccine, AstraZeneca has reportedly capitalized on the success of another.

The company has sold off its 7.7% stake in Moderna and turned it into $1.2 billion in cash, according to the Times, beefing up the reserves just as Pascal Soriot is wrapping up his $39 billion acquisition of Alexion and its rare disease pipeline.

AstraZeneca’s stock sale follows a similar move by Merck in December. But like its pharma brethren, the British giant is keeping its R&D collaborations with Moderna.

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Bob Nelsen (Photo by Michael Kovac/Getty Images)

With stars aligned and cash in re­serve, Bob Nelsen's Re­silience plans a makeover at 2 new fa­cil­i­ty ad­di­tions to its drug man­u­fac­tur­ing up­start

Bob Nelsen’s new, state-of-the-art drug manufacturing initiative is taking shape.

Just 3 months after gathering $800 million of launch money, a dream team board and a plan to shake up a field where he found too many bottlenecks and inefficiencies for the era of Covid-19, Resilience has snapped up a pair of facilities now in line for a retooling.

The company has acquired a 310,000-square-foot plant in Boston from Sanofi along with a 136,000-square-foot plant in Ontario to add to a network which CEO Rahul Singhvi says is just getting started on building his company’s operations up. The Sanofi deal comes with a contract to continue manufacturing one of its drugs.

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Af­ter bail­ing on Covid-19 vac­cines, Mer­ck will team up with J&J to pro­duce its shot as part of un­usu­al Big Phar­ma pact

Merck took a big gamble when it opted to jump into the Covid-19 vaccine race late, and made an equally momentous decision to back out in late January. Now, looking to chip in on the effort, Merck reportedly agreed to team up with one of the companies that has already crossed the finish line.

President Joe Biden on Tuesday is expected to announce a partnership between drugmakers Merck and Johnson & Johnson to jointly produce J&J’s recombinant protein Covid-19 vaccine that received the FDA’s emergency use authorization Saturday, the Washington Post reported.

Ab­b­Vie tees up a biotech buy­out af­ter siz­ing up their Parkin­son's drug spun out of Ke­van Shokat's lab

AbbVie has teed up a small but intriguing biotech buyout after looking over the preclinical work it’s been doing in Parkinson’s disease.

The company is called Mitokinin, a Bay Area biotech spun out of the lab of UCSF’s Kevan Shokat, whose scientific explorations have formed the academic basis of a slew of startups in the biotech hub. One of Shokat’s PhD students in the lab, Nicholas Hertz, co-founded Mitokinin using their lab work on PINK1 suggesting that amping up its activity could play an important role in regulating the mitochondrial dysfunction contributing to Parkinson’s disease pathogenesis and progression.

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Paul Sekhri

The next big biotech su­per­star? Paul Sekhri has some thoughts on that

It occasionally occurs to Paul Sekhri that if they pull this off, his company will be on the front page of the New York Times and a lead story in just about every major news outlet on the planet. He tries not to dwell on it, though.

“I just want to be laser-focused on getting to that point,” Sekhri says, before acknowledging, “Yes, it absolutely crossed my mind.”

Sekhri, a longtime biopharma executive with tenures at Sanofi and Novartis, is now entering year three as CEO of eGenesis, the biotech that George Church protégé Luhan Yang founded to genetically alter pigs so that they can be used for organ transplants. He led them through one megaround and has just closed another, raising $125 million from 17 different investors to push the first-ever (humanized) pig to human transplants into the clinic.

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Fi­bro­Gen shares skid low­er as a sur­prise ad­comm rais­es risks on roxa OK

FibroGen will likely have to delay its US rollout for roxadustat once again.

In an unexpected move, the FDA is convening its Cardiovascular and Renal Drugs Advisory Committee to review the NDA in an advisory committee meeting. The date is yet to be confirmed.

Just a few weeks ago, SVB Leerink analyst Geoffrey Porges predicted that the roxa approval could come ahead of the PDUFA date on March 20 — effusive despite already being let down once by the FDA’s extension of its review back in December. AstraZeneca, which is partnered with FibroGen on the chronic kidney disease-related anemia drug, disclosed regulators had requested further clarifying analyses of clinical data.

In­tro­duc­ing End­pointsF­DA+, our new pre­mi­um week­ly reg­u­la­to­ry news re­port led by Zachary Bren­nan

CRLs. 483s. CBER, CDER and RWE. For biopharma professionals, these acronyms command attention because of the fundamental role FDA plays in drug development. Now Endpoints is doubling down on regulatory coverage, and launching a weekly report focusing on developments out of White Oak, with analysis and insight into what it all means.

Coverage will be led by our new senior editor, Zachary Brennan. He joins Endpoints from POLITICO, where he covered pharma. Prior to that he was the managing editor for Regulatory Focus, a news publication from the Regulatory Affairs Professionals Society.

Amit Munshi, Arena

One of Are­na's top drugs flops in a PhI­Ib study for IBS pain. But re­searchers tease out a pos­si­ble path for­ward as CEO ex­plores 's­trate­gic op­tion­s'

Four years ago, when Arena CEO Amit Munshi cut its ties to a troubled weight drug and doubled down on the pipeline, a cannabinoid receptor 2 agonist figured prominently in the biotech’s future. On Tuesday evening, however, Munshi’s high hopes for the drug took a nasty hit after it failed a Phase IIb study for patients with irritable bowel syndrome pain.

Put through a randomized pace with 273 patients, researchers said it flat failed the primary endpoint among the large group with abdominal pain. But they quickly went on to highlight subgroup data, always a tricky and controversial ploy, where they spotlighted a positive p value for patients with moderate to severe pain who received the high dose of the drug — one of 3 provided in the study.