De­nali un­veils new way of cross­ing blood brain bar­ri­er as the big neu­ro­science bet en­ters its clin­i­cal years

Five years ago, as much of phar­ma be­gan leav­ing neu­ro­science, three big-name sci­en­tists from Genen­tech and some A-list in­vestors, in­clud­ing ARCH and Flag­ship, made a $217 mil­lion bet that new ge­net­ic in­sights and a re­liance on bio­mark­ers could bring them suc­cess. They called it De­nali Ther­a­peu­tics.

Still, De­nali faced the prob­lem that neu­ro­science de­vel­op­ers have faced for decades: How do you get a large mol­e­cule across the blood-brain bar­ri­er, a nat­ur­al de­fense evolved pre­cise­ly to keep them out? En­zyme re­place­ment ther­a­py, for in­stance, would be a great can­di­date to treat sev­er­al neu­ro­log­i­cal dis­or­ders, but en­zymes can’t cross the bar­ri­er.

Now, De­nali thinks they’ve solved the prob­lem, or at least part of it. In a pair of pa­pers pub­lished in Sci­ence Trans­la­tion­al Med­i­cine, the South San Fran­cis­co biotech de­tailed the in­ven­tion of a new trans­port ve­hi­cle to sneak large mol­e­cules past the brain’s gates. So far, it’s been used in mice and mon­keys, but they won’t wait long to bring it to pa­tients: A clin­i­cal tri­al us­ing it to re­place an en­zyme lost in peo­ple with Hunter’s syn­drome is set to be­gin this year, with proof-of-con­cept da­ta ex­pect­ed to come be­fore 2021.

The blood-brain bar­ri­er con­sists in part of tight­ly packed en­dothe­lial cells. Since cer­tain mol­e­cules, such as in­sulin, cross the bar­ri­er by first bind­ing to re­cep­tors on these cells and then be­ing al­lowed through, sci­en­tists have long tried to build an­ti­bod­ies that can sim­i­lar­ly bind to these re­cep­tors and shut­tle across a ther­a­peu­tic car­go. But the re­sults, over sev­er­al decades, have been less than trans­for­ma­tive.

Ryan Watts

CEO and founder Ryan Watts has been part of that search since his Genen­tech days. The re­search method he and De­nali’s sci­en­tists came up with be­gan with a process called di­rect­ed evo­lu­tion — in which a pro­tein is in­duced to mu­tate re­peat­ed­ly, un­til it gives rise to a pro­tein with the qual­i­ties you want — to build a pro­tein, called an FC frag­ment, that binds to what’s called a trans­fer­rin re­cep­tor, a node that nor­mal­ly im­ports iron in­to the brain. In the­o­ry, there are nu­mer­ous drugs one could then hook on­to that Fc frag­ment, but De­nali first test­ed it with an an­ti­body-tar­get­ing en­zyme called be­ta-sec­re­tase. The en­zyme is linked to the build-up of amy­loid plaques in peo­ple with Alzheimer’s, and the re­searchers showed their ve­hi­cle re­duced the amount of amy­loid in mice and mon­keys.

In a sec­ond study, the re­searchers at­tached an en­zyme called iduronate-2-sul­fa­tase, the crit­i­cal pro­tein that peo­ple with Hunter’s syn­drome are miss­ing. With­out it, sug­ars called gly­cosamino­gly­cans build up in cells, caus­ing ab­nor­mal­i­ties in sev­er­al dif­fer­ent or­gans. Shire gained ap­proval for an en­zyme re­place­ment ther­a­py in 2006, but it on­ly works out­side the brain (the com­pa­ny’s erst­while ef­forts to im­prove cog­ni­tive func­tion yield­ed lit­tle promise). Us­ing the trans­port ve­hi­cle,  though, De­nali was able to get sig­nif­i­cant­ly in­creased brain pen­e­tra­tion of the en­zyme and re­duce the pathol­o­gy in mice and mon­keys.

De­nali played up the po­ten­tial ver­sa­til­i­ty of their ap­proach over oth­er blood-brain-bar­ri­er-cross­ing pro­pos­als, such as bis­pe­cif­ic an­ti­bod­ies, say­ing you can at­tach a greater range of ther­a­pies to their ve­hi­cle. The com­pa­ny has over a dozen pro­grams — in­clud­ing a Parkin­son’s one now in the clin­ic — but the first test of the ve­hi­cle will be lat­er this year, in 16 kids with a rare dis­ease whose worst symp­toms re­main un­treat­ed.

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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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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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.

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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CEO Marco Taglietti (Scynexis)

'N­ev­er been more ur­gent:' Scynex­is looks to tack­le su­per­bug cri­sis with late-stage read­out for an­ti­fun­gal hope­ful

As the superbug crisis heats up around the world, Scynexis says it has new data from two interim analyses that prove its antifungal has the potential to treat a broad range of infections.

“The need for new anti-infectives capable of fighting the most resistant pathogens has never been more urgent as we confront the ongoing COVID-19 global pandemic,” CEO Marco Taglietti said in a statement.

A spot­light schiz­o­phre­nia drug in Neu­ro­crine's $2B Take­da deal flunks its first ma­jor test. But it's not giv­ing up yet

When Takeda spun out a pipeline of experimental psychiatry drugs to Neurocrine in a $2 billion deal amid a post-merger shakeout, R&D chief Andy Plump described the therapies as “very interesting but still difficult.”

On Tuesday, we got some idea of how difficult.

San Diego-based Neurocrine revealed that one of the three spotlight clinical programs they’d acquired failed the primary endpoint in a Phase II trial for schizophrenia, registering a negative outcome on the change from baseline in the positive and negative syndrome scale/negative symptom factor score (PANSS NSFS).

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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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.