Tired of be­ing dumped by phar­ma part­ners, Van­der­bilt’s neu­ro­science team takes a bold aim at the clin­ic

Jeff Conn

As the di­rec­tor of the Van­der­bilt Cen­ter for Neu­ro­science Drug Dis­cov­ery, Jeff Conn has spe­cial­ized in pre­clin­i­cal de­vel­op­ment work on new drugs bio­phar­ma com­pa­nies can take in­to the clin­ic. He’s al­so seen two of the big com­pa­nies he’s part­nered with — Bris­tol-My­ers Squibb and As­traZeneca — make sud­den, un­ex­pect­ed re­treats from the field, which has known a steady di­et of fail­ures and set­backs in re­cent years.

So this time, in­stead of li­cens­ing out his drug and tak­ing the risk of an­oth­er ear­ly dis­ap­pear­ance, Conn and his col­leagues at Van­der­bilt are tak­ing their drug di­rect­ly in­to an ear­ly-stage hu­man study in a rare — per­haps unique — dis­play of aca­d­e­m­ic risk-tak­ing in the clin­ic.

“This drug can­di­date is a pos­i­tive al­losteric mod­u­la­tor of an M1 (mus­carinic) re­cep­tor,” says Conn, re­fer­ring to a neu­ro­trans­mit­ter dis­rupt­ed in Alzheimer’s and schiz­o­phre­nia. This is a well plumbed field, with drugs that have been tried in the clin­ic and failed, says Conn, but no one was able to de­vel­op high­ly se­lec­tive mol­e­cules—at least not un­til now.

“That’s what we are now ad­vanc­ing,” he tells me, fo­cus­ing on cog­ni­tive im­pair­ment in ear­ly to mod­er­ate Alzheimer’s and al­so in schiz­o­phre­nia. And his team is con­cen­trat­ing on some symp­toms that haven’t been ad­dressed so far, in­clud­ing: so­cial with­draw­al, lack of mo­ti­va­tion and a lack of abil­i­ty to ex­pe­ri­ence re­ward.

“The mod­el we fo­cused on has been to part­ner with com­pa­nies rel­a­tive­ly ear­ly, cer­tain­ly be­fore clin­i­cal de­vel­op­ment,” Conn adds. “The shift­ing land­scape in the phar­ma in­dus­try (which in­clud­ed As­traZeneca’s re­cent de­ci­sion to qui­et­ly scut­tle its vir­tu­al iMed mod­el for neu­ro­science) has re­al­ly caused us to re­think that.”

“For this tar­get, we’re tak­ing it through Phase I, make sure there are none of the ad­verse ef­fect li­a­bil­i­ty seen in the ‘90s,” he adds. “That would be a ma­jor step for de-risk­ing, a good point for part­ner­ing with a ma­jor com­pa­ny. We can al­so show we could en­gage the re­cep­tor in the CNS.”

Craig Lind­s­ley

This is no small un­der­tak­ing for an aca­d­e­m­ic group, em­pha­sizes Craig Lind­s­ley, co-di­rec­tor and chief of med­i­c­i­nal chem­istry at the cen­ter.

“We all came from in­dus­try,” he notes. “Do­ing an IND on your own is quite an un­der­tak­ing, in­clud­ing tasks large­ly un­known in aca­d­e­m­ic cir­cles,” such as meet­ing rules on man­u­fac­tur­ing and prod­uct for­mu­la­tion. “It’s an ex­tra day job for every­body. It helped us un­der­stand we could do this. And next time it will be eas­i­er and faster.”

Next time will come soon enough, he says, with an ear­ly stage pipeline in the mak­ing. The NIH and non­prof­its — in­clud­ing The William K. War­ren Foun­da­tion — have pro­vid­ed the ad­di­tion­al fi­nan­cial fire­pow­er need­ed to push ahead in­to the clin­ic. Af­ter they get through Phase I, he and Conn be­lieve that they can go back and do high­er val­ue deals af­ter nail­ing down some sol­id hu­man da­ta on safe­ty and ear­ly ef­fi­ca­cy sig­nals in healthy vol­un­teers. And if Big Phar­ma isn’t in­ter­est­ed, then per­haps a small­er biotech or spin­out can do the job.

The key point, they both say, is that they want their drugs to go as far as pos­si­ble through the clin­ic, and all the way to pa­tients if they can. Next time one of their drugs fails to make it, they don’t want it to be be­cause yet an­oth­er com­pa­ny pulled a sud­den and un­ex­pect­ed left turn in their clin­i­cal strat­e­gy. And for that, they’re will­ing to as­sume some of the added risk that has fright­ened much big­ger play­ers out of the Val­ley of Death.

The top 10 block­buster drugs in the late-stage pipeline — Eval­u­ate adds 6 new ther­a­pies to heavy-hit­ter list

Vertex comes in for a substantial amount of criticism for its no-holds-barred tactical approach toward wresting the price it wants for its commercial drugs in Europe. But the flip side of that coin is a highly admired R&D and commercial operation that regularly wins kudos from analysts for their ability to engineer greater cash flow from the breakthrough drugs they create.

Both aspects needed for success in this business are on display in the program backing Vertex’s triple for cystic fibrosis. VX-659/VX-445 + Tezacaftor + Ivacaftor — it’s been whittled down to 445 now — was singled out by Evaluate Pharma as the late-stage therapy most likely to win the crown for drug sales in 5 years, with a projected peak revenue forecast of $4.3 billion.

The latest annual list, which you can see here in their latest world preview, includes a roster of some of the most closely watched development programs in biopharma. And Evaluate has added 6 must-watch experimental drugs to the top 10 as drugs fail or go on to a first approval. With apologies to the list maker, I revamped this to rank the top 10 by projected 2024 sales, instead of Evaluate's net present value rankings.

It's how we roll at Endpoints News.

Here is a quick summary of the rest of the top 10:

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John Reed at JPM 2019. Jeff Rumans for Endpoints News

Sanofi's John Reed con­tin­ues to re­or­ga­nize R&D, cut­ting 466 jobs while boost­ing can­cer, gene ther­a­py re­search

The R&D reorganization inside Sanofi is continuing, more than a year after the pharma giant brought in John Reed to head the research arm of the Paris-based company.
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How small- to mid-sized biotechs can adopt pa­tient cen­tric­i­ty in their on­col­o­gy tri­als

By Lucy Clos­sick Thom­son, Se­nior Di­rec­tor of On­col­o­gy Pro­ject Man­age­ment, Icon

Clin­i­cal tri­als in on­col­o­gy can be cost­ly and chal­leng­ing to man­age. One fac­tor that could re­duce costs and re­duce bar­ri­ers is har­ness­ing the pa­tient voice in tri­al de­sign to help ac­cel­er­ate pa­tient en­roll­ment. Now is the time to adopt pa­tient-cen­tric strate­gies that not on­ly fo­cus on pa­tient needs, but al­so can main­tain cost ef­fi­cien­cy.

In­vestor day prep at Mer­ck in­cludes a new strat­e­gy to pick up the pace on M&A — re­port

Mer­ck’s re­cent deals to buy up two bolt-on biotechs — Ti­los and Pelo­ton — weren’t an aber­ra­tion. In­stead, both ac­qui­si­tions mark a new strat­e­gy to beef up its dom­i­nant can­cer drug op­er­a­tions cen­tered on Keytru­da while look­ing to ad­dress grow­ing con­cerns that too many of its eggs are in the one I/O bas­ket for their PD-1 pro­gram. And Mer­ck is go­ing af­ter more small- and mid-sized buy­outs to calm those fears.

John Chiminski, Catalent CEO - File Photo

'It's a growth play': Catal­ent ac­quires Bris­tol-My­er­s' Eu­ro­pean launch pad, ex­pand­ing glob­al CD­MO ops

Catalent is staying on the growth track.

Just two months after committing $1.2 billion to pick up Paragon and take a deep dive into the sizzling hot gene therapy manufacturing sector, the CDMO is bouncing right back with a deal to buy out Bristol-Myers’ central launchpad for new therapies in Europe, acquiring a complex in Anagni, Italy, southwest of Rome, that will significantly expand its capacity on the continent.

There are no terms being offered, but this is no small deal. The Anagni campus employs some 700 staffers, and Catalent is planning to go right in — once the deal closes late this year — with a blueprint to build up the operations further as they expand on oral solid, biologics, and sterile product manufacturing and packaging.

This is an uncommon deal, Catalent CEO John Chiminski tells me. But it offers a shortcut for rapid growth that cuts years out of developing a green fields project. That’s time Catalent doesn’t have as the industry undergoes unprecedented expansion around the world.

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Right back at you, Pfiz­er: BeiGene and a Pfiz­er spin­out launch a new­co to de­vel­op a MEK/BRAF in­hibitor that could ri­val $11.4B com­bo

A day af­ter Pfiz­er bought Ar­ray and its ap­proved can­cer com­bo, BeiGene and Pfiz­er spin­out Spring­Works have part­nered in launch­ing a new biotech that has an eye on the very same mar­ket the phar­ma gi­ant just paid bil­lions for. And they’re plan­ning on us­ing an ex-Pfiz­er drug to do it.

In a nut­shell, Chi­na’s BeiGene is toss­ing in a pre­clin­i­cal BRAF in­hibitor — BGB-3245, which cov­ers both V600 and non-V600 BRAF mu­ta­tions — for a big stake in a new, joint­ly con­trolled biotech called Map­Kure with Bain-backed Spring­Works.

Sanofi aligns it­self with Google to stream­line drug de­vel­op­ment

Tech­nol­o­gy is bleed­ing in­to health­care, and big phar­ma is rid­ing the wave. Sanofi $SNY ap­point­ed its first chief dig­i­tal of­fi­cer this Feb­ru­ary, fol­low­ing the foot­steps of its peers. By May, the French drug­mak­er and some of its big phar­ma com­pa­tri­ots joined forces with Google par­ent Al­pha­bet’s Ver­i­ly unit to aug­ment clin­i­cal tri­al re­search. On Tues­day, the Parisian com­pa­ny tied up with Google to ac­cess its cloud com­put­ing and ar­ti­fi­cial in­tel­li­gence tech to spur the de­vel­op­ment of new ther­a­pies.

UP­DAT­ED: Roche fields first ap­proval for Ro­z­lytrek in the run-up to a show­down with Bay­er, Pfiz­er

While it’s wait­ing to hear back from FDA reg­u­la­tors, Roche is be­gin­ning the vic­to­ry lap for en­trec­tinib in Japan.

Roche is giv­ing Bay­er a run for their mon­ey with this tu­mor-ag­nos­tic drug, which tar­gets NTRK gene fu­sions. Now dubbed Ro­z­lytrek, it’s sanc­tioned to treat adult and pe­di­atric pa­tients in Japan with neu­rotroph­ic ty­ro­sine re­cep­tor ki­nase fu­sion-pos­i­tive, ad­vanced re­cur­rent sol­id tu­mors.

Arc­turus ex­pands col­lab­o­ra­tion, adding $30M cash; Ku­ra shoots for $100M raise

→  Rare dis­ease play­er Ul­tragenyx $RARE is ex­pand­ing its al­liance with Arc­turus $ARCT, pay­ing $24 mil­lion for eq­ui­ty and an­oth­er $6 mil­lion in an up­front as the two part­ners ex­pand their col­lab­o­ra­tion to in­clude up to 12 tar­gets. “This ex­pand­ed col­lab­o­ra­tion fur­ther so­lid­i­fies our mR­NA plat­form by adding ad­di­tion­al tar­gets and ex­pand­ing our abil­i­ty to po­ten­tial­ly treat more dis­eases,” said Emil Kakkis, the CEO at Ul­tragenyx. “We are pleased with the progress of our on­go­ing col­lab­o­ra­tion. Our most ad­vanced mR­NA pro­gram, UX053 for the treat­ment of Glyco­gen Stor­age Dis­ease Type III, is ex­pect­ed to move in­to the clin­ic next year, and we look for­ward to fur­ther build­ing up­on the ini­tial suc­cess of this part­ner­ship.”