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.

At the In­flec­tion Point for the Next Gen­er­a­tion of Can­cer Im­munother­a­py

While oncology researchers have long pursued the potential of cellular immunotherapies for the treatment of cancer, it was unclear whether these therapies would ever reach patients due to the complexity of manufacturing and costs of development. Fortunately, the recent successful development and regulatory approval of chimeric antigen receptor-engineered T (CAR-T) cells have demonstrated the significant benefit of these therapies to patients.

Stéphane Bancel, Moderna CEO

'This is not go­ing to be good': Mod­er­na CEO Ban­cel warns of a 'ma­te­r­i­al drop' in vac­cine ef­fi­ca­cy as Omi­cron spreads

Even as public health officials remain guarded about their comments on the likelihood Omicron will escape the reach of the currently approved Covid-19 vaccines, there’s growing scientific consensus that we’re facing a variant that threatens to overwhelm the vaccine barricades that have been erected.

Stéphane Bancel, the CEO of Moderna, one of the leading mRNA players whose quick vault into the markets with a highly effective vaccine created an instant multibillion-dollar market, added his voice to the rising chorus early Tuesday. According to Bancel, there will be a significant drop in efficacy when the average immune system is confronted by Omicron. The only question now is: How much?

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Ap­peals court puts the fi­nal nail in the cof­fin for Tec­fidera patent, adding to Bio­gen's bur­geon­ing set­backs

In another setback for Biogen, the big biotech lost its appeal to revive a patent for the once-blockbuster drug Tecfidera, marking a likely conclusion to the case.

The US Court of Appeals for the Federal Circuit issued the ruling Tuesday morning, saying Biogen failed to satisfy the “written description” requirement for patent law. As a result, Mylan-turned-Viatris will be able to sell its multiple sclerosis generic without fear of infringement and Biogen will have to find a new revenue driver elsewhere.

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Philip Dormitzer, new GSK global head of vaccines R&D

Glax­o­SmithK­line poach­es Pfiz­er's vi­ral vac­cines lead in rush to cap­i­tal­ize on fu­ture of mR­NA

GlaxoSmithKline has appointed Philip Dormitzer, formerly chief scientific officer of Pfizer’s viral vaccines unit, as its newest global head of vaccines R&D, looking to leverage one of the leading minds behind Pfizer and BioNTech’s RNA collaboration that led to Covid-19 jab Comirnaty, the British drug giant said Tuesday.

Dormitzer had been with Pfizer for a little more than six years, joining up after a seven-year stint with Novartis, where he reached the role of US head of research and head of global virology for the company’s vaccines and diagnostics unit.

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In­tro­duc­ing End­points Stu­dio, a new way to ad­ver­tise with End­points-craft­ed brand­ing cam­paigns

Since our start in 2016, Endpoints has grown fast while executing our mission to cover biopharma’s most critical developments for industry pros worldwide. As readership has grown, our advertising business has too. Endpoints advertising partners support the mission and engage their desired audiences through announcements on our email and web platforms, brand recognition in our event coverage and sponsorships of Endpoints daily and weekly reports.

As lead drug runs in­to a wall, De­ci­phera slims down its pipeline, puts 140 jobs on the chop­ping block

Barely a month after disappointing data shattered hopes for a major label expansion for the GI tumor drug Qinlock, Deciphera is making a major pivot — scrapping development plans for that drug and discarding another while it hunkers down and focuses on two remaining drugs in the pipeline.

As a result, 140 of its staffers will be laid off.

The restructuring, which claims the equivalent of 35% of its total workforce, will take place across all departments including commercial, R&D as well as general and administrative support functions, Deciphera said, as it looks to streamline Qinlock-related commercial operations in the US while concentrating only on a “select number of key European markets.”

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How to use reg­istry da­ta to sup­port FDA de­ci­sion mak­ing: Agency ex­plains in new guid­ance

Drugmakers looking to design a new registry or use an existing one to support a regulatory decision on a drug’s effectiveness or safety will need to consult with a new draft guidance released Monday by the FDA.

The agency’s reliance on registry data for regulatory decisions dates back more than two decades, at least, as in 1998 Bayer won approval for its anticoagulant Refludan (withdrawn from the market in 2013 for commercial reasons) based in part on a historical control group pulled from a registry.

Tillman Gerngross (Adagio)

Till­man Gern­gross on Omi­cron: 'It is a grim sit­u­a­tion...we’re go­ing to see a sig­nif­i­cant drop in vac­cine ef­fi­ca­cy'

Tillman Gerngross, the rarely shy Dartmouth professor, biotech entrepreneur and antibody expert, has been warning for over a year that the virus behind Covid-19 would likely continue to mutate, potentially in ways that avoid immunity from infection and the best defenses scientists developed. He spun out a company, Adagio, to build a universal antibody, one that could snuff out any potential mutation.

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In­cor­po­rat­ing Ex­ter­nal Da­ta in­to Clin­i­cal Tri­als: Com­par­ing Dig­i­tal Twins to Ex­ter­nal Con­trol Arms

Most drug development professionals are familiar with the nerve-racking wait for the read-out of a large trial. If it’s negative, is the investigational therapy ineffective? Or could the failure result from an unforeseen flaw in the design or execution of the protocol, rather than a lack of efficacy? The team could spend weeks analyzing data, but a definitive answer may be elusive due to insufficient power for such analyses in the already completed trial. These problems are only made worse if the trial had lower enrollment, or higher dropout than expected due to an unanticipated event like COVID-19. And if a trial is negative, the next one is likely to be larger and more costly — if it happens at all.