Gene ther­a­py pi­o­neer James Wil­son sounds an alarm on high-dose AAV stud­ies fol­low­ing tox­ic re­ac­tions in mon­keys

James Wil­son. Penn News

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Penn pro­fes­sor James Wil­son is one of the pre­em­i­nent sci­en­tists work­ing to­day in gene ther­a­py. He’s al­so the key fig­ure in a fa­tal gene ther­a­py tri­al back in the late ’90s that left the field in lim­bo for years, un­til a new gen­er­a­tion of biotechs hus­tled ahead with the cur­rent wave of vec­tor-car­ried cor­rec­tive genes in the clin­ic — with an his­toric first ap­proval in the US for Spark.

So when it sur­faced that Wil­son had quit an ad­vi­so­ry role at Sol­id Bio $SLDB over safe­ty is­sues as­so­ci­at­ed with high-dose AAV gene ther­a­py treat­ments — which co­in­cid­ed with a par­tial FDA hold on Sol­id’s high-dose work that was an­nounced just hours be­fore it priced its $125 mil­lion IPO — that sound­ed an alarm to some peo­ple in the field.

On Mon­day, Wil­son and his team un­veiled the rea­sons for his safe­ty con­cerns in an on­line pub­li­ca­tion of a new an­i­mal study that out­lined their use of a high-dose AAV de­liv­ery of a cor­rec­tive gene for the sur­vival of mo­tor neu­ron (SMN) pro­tein.

Fol­low­ing suc­cess­ful work in­volv­ing in­fants with spinal mus­cu­lar at­ro­phy, a link that al­so dinged AveX­is $AVXS to­day, Wil­son and his team at Penn want­ed to see how the same ap­proach could cor­rect a ge­net­ic de­fi­cien­cy of low­er mo­tor neu­rons — a con­di­tion linked to neu­ro­mus­cu­lar dis­eases.

The an­i­mal study, us­ing three rhe­sus macaque mon­keys and three pigs, was a tox­ic dis­as­ter.

Four days af­ter one of the macaques had re­ceived 2×1014 GC/kg AAVhu68 vec­tor ex­press­ing hu­man SMN, the mon­key ex­pe­ri­enced a se­vere cri­sis, go­ing in­to shock af­ter suf­fer­ing se­vere liv­er dam­age, which forced re­searchers to eu­th­a­nize the pri­mate. The two oth­er macaques sur­vived, but al­so suf­fered a tox­ic re­ac­tion.

All three piglets treat­ed with a high, sys­temic IV dose were al­so eu­th­a­nized, with the first ex­pe­ri­enc­ing atax­ia and the oth­er two re­spond­ing with neu­ro­log­i­cal symp­toms.

“The ad­verse events ob­served in these two NHP (non­hu­man pri­mate) stud­ies pro­vide provoca­tive but in­com­plete ev­i­dence for a uni­fy­ing mech­a­nism of tox­i­c­i­ty re­sult­ing from high dose sys­temic AAV ad­min­is­tra­tion,” the team writes. “Find­ings com­mon to both ex­per­i­ments in­clude he­pa­to­cel­lu­lar in­jury and de­vel­op­ment of a bleed­ing diathe­sis con­sis­tent with DIC with­in 5 days of vec­tor ad­min­is­tra­tion. It is present­ly un­clear whether liv­er dam­age is the pri­ma­ry in­sult lead­ing to the co­ag­u­lopa­thy, or if the co­ag­u­lopa­thy is a man­i­fes­ta­tion of sys­temic tox­i­c­i­ty that re­sults in sec­ondary liv­er dam­age.”

And there’s this:

Go­ing for­ward we sug­gest that clin­i­cal tri­als of high dose sys­temic AAV in­clude care­ful pre‐clin­i­cal vet­ting in NH­Ps and ear­ly lab­o­ra­to­ry and clin­i­cal eval­u­a­tions for sys­temic tox­i­c­i­ty, liv­er dam­age, and co­ag­u­lopa­thy as well as de­layed symp­toms of sen­so­ry neu­ropa­thy.

Sol­id Bio says it is out to cure Duchenne MD us­ing a gene ther­a­py. And af­ter see­ing its IPO get start­ed with a quick peak, the stock slipped from its high but was still trad­ing well over its ini­tial price. As news of the study spread, though, the stock plunged 12% on Tues­day. Shares of Re­genxbio $RGNX, where Wil­son has pro­vid­ed much of the AAV patent work, slid 4%.

What­ev­er wor­ries Wil­son may have now about high-dose AAV work, the biotechs in the field have yet to see much of it spread among the in­vestors who back their com­pa­nies.

Nick Leschly via Getty

UP­DAT­ED: Blue­bird shares sink as an­a­lysts puz­zle out $1.8M stick­er shock and an un­ex­pect­ed de­lay

Blue­bird bio $BLUE has un­veiled its price for the new­ly ap­proved gene ther­a­py Zyn­te­glo (Lenti­Glo­bin), which came as a big sur­prise. And it wasn’t the on­ly un­ex­pect­ed twist in to­day’s sto­ry.

With some an­a­lysts bet­ting on a $900,000 price for the β-tha­lassemia treat­ment in Eu­rope, where reg­u­la­tors pro­vid­ed a con­di­tion­al ear­ly OK, blue­bird CEO Nick Leschly said Fri­day morn­ing that the pa­tients who are suc­cess­ful­ly treat­ed with their drug over 5 years will be charged twice that — $1.8 mil­lion — on the con­ti­nent. That makes this drug the sec­ond most ex­pen­sive ther­a­py on the plan­et, just be­hind No­var­tis’ new­ly ap­proved Zol­gens­ma at $2.1 mil­lion, with an­a­lysts still wait­ing to see what kind of pre­mi­um can be had in the US.

Neil Woodford, Woodford Investment Management via YouTube

Un­der siege, in­vest­ment man­ag­er Wood­ford faces an­oth­er in­vest­ment shock

Em­bat­tled UK fund man­ag­er Neil Wood­ford — who has con­tro­ver­sial­ly blocked in­vestors from pulling out from his flag­ship fund to stem the blood­let­ting, af­ter a slew of dis­ap­point­ed in­vestors fled fol­low­ing a se­ries of sour bets — is now pay­ing the price for his ac­tions via an in­vestor ex­o­dus on an­oth­er fund.

Har­g­reaves Lans­down, which has in the past sold and pro­mot­ed the Wood­ford funds via its re­tail in­vest­ment plat­form, has re­port­ed­ly with­drawn £45 mil­lion — its en­tire po­si­tion — from the in­vest­ment man­ag­er’s In­come Fo­cus Fund.

Ted Love. HAVERFORD COLLEGE

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News­mak­ers at #EHA19: Re­gen­eron, Ar­Qule track progress on re­sponse rates

Re­gen­eron’s close­ly-watched bis­pe­cif­ic con­tin­ues to ring up high re­sponse rates

Re­gen­eron’s high-pro­file bis­pe­cif­ic REGN1979 is back in the spot­light at the Eu­ro­pean Hema­tol­ogy As­so­ci­a­tion sci­en­tif­ic con­fab. And while the stel­lar num­bers we saw at ASH have erod­ed some­what as more blood can­cer pa­tients are eval­u­at­ed, the re­sponse rates for this CD3/CD20 drug re­main high.

A to­tal of 13 out of 14 fol­lic­u­lar lym­phomas re­spond­ed to the drug, a 93% ORR, down from 100% at the last read­out. In 10 out of 14, there was a com­plete re­sponse. In dif­fuse large B-cell lym­phoma the re­sponse rate was 57% among pa­tients treat­ed at the 80 mg to 160 mg dose range. They were all com­plete re­spons­es. And 2 of these Cars were for pa­tients who had failed CAR-T ther­a­py.

Gene ther­a­pies seize the top of the list of the most ex­pen­sive drugs on the plan­et — and that trend has just be­gun

Anyone looking for a few simple reasons why the gene therapy field has caught fire with the pharma giants need only look at the new list of the 10 most expensive therapies from GoodRx.

Two recently approved gene therapies sit atop this list, with Novartis’ Zolgensma crowned the king of the priciest drugs at $2.1 million. Right below is Luxturna, the $850,000 pioneer from Spark, which Roche is pushing hard to acquire as it adds a gene therapy group to the global mix.

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→ Gilead has turned to Van­cou­ver-based Ab­Cellera for its lat­est dis­cov­ery deal. Ab­Cellera will use its know-how in “sin­gle-cell screen­ing of nat­ur­al im­mune sources” to find an­ti­body can­di­dates for Gilead to pur­sue in the in­fec­tious dis­ease field. The deal in­cludes an up­front and mile­stones.

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In cov­er­ing that bit of an­ti-Big Phar­ma fan­ta­sy — there are lots of rea­sons to go af­ter phar­ma, but this piece was lu­di­crous — I not­ed com­ments in the sto­ry from some promi­nent peo­ple in the field crit­i­ciz­ing Pfiz­er for not pub­lish­ing the da­ta. I sin­gled out Rudy Tanzi at Har­vard and then ap­plied some added crit­i­cism for the things he’s done to hype — in my opin­ion — high­ly ques­tion­able as­sump­tions. You can see it in the link. 

J&J gains an en­thu­si­as­tic en­dorse­ment from Pres­i­dent Don­ald Trump for their big new drug Spra­va­to

Pres­i­dent Don­ald Trump has lit­tle love for Big Phar­ma, but there’s at least one new drug that just hit the mar­ket which he is en­am­ored with.

Trump, ev­i­dent­ly, has been read­ing up on J&J’s new an­ti-de­pres­sion drug, Spra­va­to. And the pres­i­dent — who of­ten likes to break out in­to a full-throat­ed at­tack on greedy drug­mak­ers — ap­par­ent­ly en­thused about the ther­a­py in a meet­ing with of­fi­cials of Vet­er­ans Af­fairs, which has long grap­pled with de­pres­sion among vet­er­ans.

Fol­low­ing CAR-T pi­o­neer­s' foot­steps, Tes­sa launch­es Chi­na JV in $120M deal

These days just about every biotech se­ri­ous about glob­al de­vel­op­ment — and not just com­mer­cial­iza­tion — has a Chi­na strat­e­gy. Tes­sa Ther­a­peu­tics, a Bay­lor as­so­ci­at­ed out­fit based out of Sin­ga­pore, is no ex­cep­tion.

Tak­ing a page out of the CAR-T pi­o­neers’ play­book, Tes­sa is es­tab­lish­ing a joint ven­ture with Chi­na-Sin­ga­pore Guangzhou Knowl­edge City, which is ini­tial­ly putting down $40 mil­lion for a 13% stake with $40 mil­lion more to come in a sec­ond stage. The biotech, which now re­tains an 87% con­trol, is al­so rolling out its own con­tri­bu­tions in two phas­es, start­ing with $20 mil­lion and all its tech­nol­o­gy li­cense rights for Chi­na.