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.

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We­bi­nar: Re­al World End­points — the brave new world com­ing in build­ing fran­chise ther­a­pies

Several biopharma companies have been working on expanding drug labels through the use of real world endpoints, combing through the data to find evidence of a drug’s efficacy for particular indications. But we’ve just begun. Real World Evidence is becoming an important part of every clinical development plan, in the soup-through-nuts approach used in building franchises.

I’ve recruited a panel of 3 top experts in the field — the first in a series of premium webinars — to look at the practical realities governing what can be done today, and where this is headed over the next few years, at the prodding of the FDA.

ZHEN SU — Merck Serono’s Senior Vice President and Global Head of Oncology
ELLIOTT LEVY — Amgen’s Senior Vice President of Global Development
CHRIS BOSHOFF — Pfizer Oncology’s Chief Development Officer

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Brian Kaspar. AveXis via Twitter

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But in his first public response, the scientific founder at AveXis — acquired by Novartis for $8.7 billion — is firing back. And he says that not only was he not involved in any wrongdoing, he’s ready to defend his name as needed.

I reached out to Brian Kaspar after Novartis put out word that he and his brother Allen had been axed in mid-May, two months after the company became aware of the allegations related to manipulated data. His response came back through his attorneys.

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Hal Barron. GSK

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It’s hard to overestimate the importance of this drug for GSK, a cornerstone of Barron’s campaign to make a dramatic impact on the oncology market and provide some long-lost excitement for the pharma giant’s pipeline. They’re putting this BCMA program at the front of that charge — looking to lead a host of rivals all aimed at the same target.

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That marks another step down on price for a PRV, which allows the holder to slash 4 months off of any FDA review time.

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