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.

Mi­no­ryx and Sper­o­genix ink an ex­clu­sive li­cense agree­ment to de­vel­op and com­mer­cial­ize lerigli­ta­zone in Chi­na

September 23, 2020 – Hong Kong, Beijing, Shanghai (China) and Mataró, Barcelona (Spain)  

Minoryx will receive an upfront and milestone payments of up to $78 million, as well as double digit royalties on annual net sales 

Sperogenix will receive exclusive rights to develop and commercialize leriglitazone for the treatment of X-linked adrenoleukodystrophy (X-ALD), a rare life-threatening neurological condition

(L-R) Dr. Robert Redfield, director of the Centers for Disease Control and Prevention; Dr. Anthony Fauci, director of the National Institute for Allergy and Infectious Diseases; Adm. Brett P. Giroir, Assistant Secretary for Health; and Dr. Stephen M. Hahn, commissioner of the Food and Drugs Administration prepare to testify at a hearing of the House Committee on Energy and Commerce on Capitol Hill on June 23, 2020 in Washington, DC. The committee is investigating the Trump administration's response to the COVID-19 pandemic. (Photo by Kevin Dietsch-Pool/Getty Images)

Trump neuters FDA's at­tempt to strength­en vac­cine guide­lines, call­ing it 'ex­treme­ly po­lit­i­cal'

Stephen Hahn went before a Senate committee Wednesday and declared he’s fighting. “Every one of the decisions we have reached has been made by career FDA scientists based on science and data, not politics,” he exclaimed, adding that “FDA will not permit any pressure from anyone to change that. I will fight for science.”

A few hours later, he was undermined by President Donald Trump when a reporter asked if he was okay with stricter vaccine guidelines that the FDA was said to be cooking up. “That has to be approved by the White House. We may or may not approve it. That sounds like a political move,” he decided.

CEO Markus Warmuth (Monte Rosa)

Monte Rosa rakes in $96M Se­ries B as it pre­pares 'mol­e­c­u­lar glue' plat­form for IND-en­abling stud­ies

About four months after completing an extension to its Series A, Monte Rosa Therapeutics is putting its next foot forward with another heap of cash.

The Boston-based biotech is back with $96 million in Series B financing with a goal to get its lead program ready for IND-enabling studies by the end of the year. Though Monte Rosa is keeping its specific target a secret for now, the company has been researching how to utilize its protein degradation technology in breast cancer and non-small cell lung cancer, among other areas.

Vas Narasimhan (AP Images)

UP­DAT­ED: Still held down by clin­i­cal hold, No­var­tis' Zol­gens­ma falls fur­ther be­hind Bio­gen and Roche as FDA asks for a new piv­otal study

Last October, the FDA slowed down Novartis’ quest to extend its gene therapy to older spinal muscular atrophy patients by slapping a partial hold on intrathecal administration. Almost a year later, the hold is still there, and regulators are adding another hurdle required for regulatory submission: a new pivotal confirmatory study.

The new requirement — which departs significantly from Novartis’ prior expectations — will likely stretch the path to registration beyond 2021, when analysts were expecting a BLA submission. That could mean more time for Biogen to reap Spinraza revenues and Roche to ramp up sales of Evrysdi in the absence of a rival.

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David Berry (Flagship)

Flag­ship's next big tech­no­log­i­cal bet? The cloud

Earlier this month, Flagship announced their big bet on the software half the industry is talking about, launching the AI and machine learning startup. Now, they and a couple other investors are gambling $100 million on a software that much of the public generally thinks of as a cool, IT afterthought: cloud computing.

The idea, says founder and Flagship partner David Berry, is one of scale: The sheer magnitude of biological data that you can store on cloud technology is unprecedented. And that size, when leveraged properly, can allow you to ask questions and form insights that are similarly unprecedented.

Jim Roberts and Brian Finrow (Lumen Bioscience)

With a $4M fed­er­al grant, Lu­men jumps in­to the Covid-19 treat­ment race

It’s been less than a month since Lumen Bioscience announced a $16 million Series B to engineer spirulina — a nutrient-packed super food — for diseases like traveler’s diarrhea, norovirus and C. difficile colitis. And now, the biotech has pulled in another $4 million to do the same for Covid-19.

The approach is quite similar to other gastrointestinal targets the company is pursuing, co-founders and Brian Finrow and Jim Roberts said. The Seattle-based company is working on a camelid antibody cocktail to combat GI infection common among Covid-19 patients. In a study published in the American Journal of Gastroenterology, a majority of Covid-19 patients showed GI and respiratory symptoms, and 25% had only GI symptoms.

FDA commissioner Stephen Hahn at the White House (AP Images)

Un­der fire, FDA to is­sue stricter guid­ance for Covid-19 vac­cine EUA this week — re­port

The FDA has been insisting for months that a Covid-19 vaccine had to be at least 50% effective – a measure of transparency meant to shore public trust in the agency and in a vaccine that had been brought forward at record speed and record political pressure. But now, with concerns of a Trump-driven authorization arriving before the election, the agency may be raising the bar.

The FDA is set to release new guidance that would raise safety and efficacy requirements for a vaccine EUA above earlier guidance and above the criteria used for convalescent plasma or hydroxychloroquine, The Washington Post reported. Experts say this significantly lowers the odds of an approval before the election on November 3, which Trump has promised despite vocal concerns from public health officials, and could help shore up public trust in the agency and any eventual vaccine.

PhII Alzheimer's fail­ure deals new blow to Roche, AC Im­mune — but the tau hy­poth­e­sis is far from dead

The leading anti-tau antibody has failed its first Phase II testing, casting a shadow on a popular target (just trailing amyloid beta) for Alzheimer’s disease.

Roche and AC Immune are quick to acknowledge disappointment in the topline readout, which suggested that semorinemab did not reduce cognitive decline among patients with early Alzheimer’s disease, who are either just starting to have symptoms or have mild manifestations.

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Samit Hirawat (Bristol Myers Squibb)

Af­ter bruis­ing re­jec­tion, blue­bird and Bris­tol My­ers Squibb land ide-cel pri­or­i­ty re­view. But will it mat­ter for the CVR?

With the clock all but up, the FDA accepted and handed priority review to Bristol Myers Squibb and bluebird bio’s BCMA CAR-T, keeping a narrow window open for Celgene investors to still cash in on the $9 CVR from the $63 billion Celgene merger.

The acceptance comes five months after the two companies weres slammed with a surprise refuse-to-file that threatened to foreclose the CVR entirely. Today’s acceptance sets the FDA decision date for March 27, 2021 – or precisely 4 days before the CVR deadline of March 31. Given the breakthrough designation and strong pivotal data — 81.5% response rate, 35.2% complete response rate — priority review was largely expected.

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