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

The 20 un­der 40: In­side the next gen­er­a­tion of bio­phar­ma lead­ers

“Each generation needs a new music,” Francis Crick wrote in 1988, reflecting back on his landmark discovery. Crick was 35, then, in 1953, when he began working with a 23-year-old named James Watson, and 37 when the pair unveiled the double helix. Rosalind Franklin, whose diffraction work undergirded their metal model, was 32.

The model would become the score for a new era in biology, one devoted to cracking the basic structures turning inside life. Subsequent years would bring new conductors and new rhythms: Robert Swanson, 29 when he convinced a 39-year-old Herb Boyer to build a company off his work and call it Genentech; Phillip Sharp, 29 when he discovered RNA splicing and 34 when he co-founded Biogen; Frances Arnold, 36 when she pioneered directed evolution; Feng Zhang, 31 when he published his CRISPR paper.

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FDA Commissioner Stephen Hahn and President Donald Trump at a press briefing on March 19, 2020. (AP Images)

Biotech ex­ecs warn that the FDA is fum­bling their re­sponse to the Covid-19 open-door promise, de­lay­ing progress

A few days ago the FDA touted a procedure for Covid-19 meds that committed the agency to immediate action for developers, formalizing a high-speed response that’s been promised for weeks.

Bioregnum Opinion Column by John Carroll

Decisions that once required months would be measured in hours under the Coronavirus Treatment Acceleration Program. “In many cases” trial protocols could be hammered out in less than a single day. If you had a potential solution to the crisis, the appropriate staffer would be in touch “to get studies underway quickly.”

It would be the ultimate high-speed regulatory pathway from Phase I to approval. Red tape was banished.

But it’s clear that for some — and quite likely many — biopharma execs, the actual agency response has not measured up to the promise. Beyond the front ranks of advanced companies in the field, like Gilead, or for drugs endorsed by President Trump, it may not even come close.

“The first response is this form letter everyone gets,” says one biotech CEO who’s reached out to the FDA on Covid-19. And when you try to cut through that, the ball gets dropped as it is passed from top officials to the frontline staff actually charged with getting things done.

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An­oth­er day, an­oth­er boat­load for biotech. Deer­field adds $840M to rush of ven­ture dol­lars

The biotech dollars just keep rolling in.

Even as the world economy faces an economic contraction unprecedented in nature, biotech venture capital firms are announcing huge new investment pots. The latest? Deerfield Management Co.

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Small mol­e­cules, bi­o­log­ics and now gene ther­a­pies: Ger­many's Evotec adds an­oth­er feath­er to its R&D cap

German drug discovery company Evotec — which has a thriving rolodex of biopharma partners such as Bayer, Boehringer Ingelheim, Novartis, Novo Nordisk, Pfizer, Sanofi, and Takeda — is now venturing into gene therapies.

The company swallowed Seattle-based Just Biotherapeutics, a company focused on reducing the cost of manufacturing protein therapies last year. It is now setting up a dedicated R&D site for gene therapies in Austria, in an effort to achieve a “modality-agnostic” repertoire — small molecules, biologics and now gene therapies.

A pair of PhI­II fail­ures spells last rites for Men­lo’s once-promis­ing Mer­ck drug

Four months after an intercontinental merger, Menlo Therapeutics is counting yet another pair of trial failures — ones with significant consequences for the companies, their shareholders and the drug.

In two pivotal Phase III trials, Menlo’s lead drug serlopitant failed to treat pruritus associated with prurigo nodularis — basically itchiness from a particular skin disease that causes red lesions on a person’s arms or legs. Serlopitant has long been the company’s only drug and as recently as 2018, it looked promising enough to support a stock price of $37. In April of that year, a Phase II failure demolished the stock price overnight: $35 to $9. Other subsequent stumbles trickled the ticker down to just above $2.

Af­ter putting aside a bit­ter le­gal feud, Al­ny­lam and Dicer­na chiefs make nice with an RNAi col­lab­o­ra­tion

John Maraganore and Douglas Fambrough used to be at each other’s throats as Alnylam pursued claims that its RNAi rivals at Dicerna had improperly purloined the IP it had picked up from Merck in a bargain basement fire sale.

But that was all settled up close to 2 years ago with a settlement from Dicerna’s Fambrough. And now the two are moving ahead in a close R&D partnership that makes them collaborators on a couple of key disease targets.

GSK's Hal Bar­ron buys a $250M stake in George Scan­gos' Vir and makes a bee­line to the clin­ic with Covid-19 an­ti­bod­ies

GlaxoSmithKline is diving straight into the swirling waters of Covid-19 R&D work, and investing $250 million to grab a chunk of equity in one of the emerging stars in infectious disease research to make it official.

GSK put out word this morning that it is partnering with Vir Biotechnology $VIR, the infectious disease startup founded in the Bay Area by former Biogen CEO George Scangos. They’re planning a leap into Phase II studies for 2 preclinical antibody candidates — VIR-7831 and VIR-7832 — that have been engineered to target the SARS-CoV-2 spike protein.

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Gilead CEO Daniel O'Day attends a meeting with the President and other biopharma leaders at the White House on March 2, 2020 (AP Photo)

Ramp­ing up glob­al pro­duc­tion of remde­sivir, Gilead CEO Dan O’Day de­tails plans to dis­trib­ute 1.5M dos­es to fight Covid-19 — for free

Gilead is still some days away from turning the card on its first round of data on remdesivir’s ability to fight severe cases of Covid-19, but the big biotech is ramping up an emergency supply of a million courses of therapy as it starts free distribution of the drug to tens of thousands of patients under their compassionate use and expanded access program as well as clinical trials.

In his latest open letter posted over the weekend, Gilead CEO Dan O’Day outlined how the company has been successful in cutting production time on remdesivir while repurposing some of their own facilities and turning to contract manufacturers to build a near-term supply of 1.5 million doses. They are still working on efficacy and dosing, but that supply could cover 140,000 courses of treatment. That supply, he added, would be more widely available following a potential approval.

Covid-19 roundup: In­ovio gets FDA green­light to en­ter hu­man tri­als; Trump push­es untest­ed malar­ia drugs again

Inovio, one of the clutch of companies working on a Covid-19 vaccine, has been cleared by the FDA to kick off in-human studies of its experimental vaccine candidate. The Pennsylvania company secured funding from the Coalition for Epidemic Preparedness Innovations (CEPI) and the Bill and Melinda Gates Foundation to support its effort.

The trial testing the DNA vaccine, INO-4800, in up to 40 healthy volunteers is set to begin this week, and the first dose is planned to be administered today. Each participant will receive two doses of INO-4800 a month apart, and the initial immune responses and safety data from the study are expected by late summer, the company said. Shares of Inovio — which in four decades of existence has not successfully developed a product — $INO jumped about 11% to $8.60 in premarket trading.