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.

UP­DAT­ED: Mer­ck pulls Keytru­da in SCLC af­ter ac­cel­er­at­ed nod. Is the FDA get­ting tough on drug­mak­ers that don't hit their marks?

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Merck has withdrawn its marketing approval for PD-(L)1 inhibitor Keytruda in metastatic small cell lung cancer as part of what it describes as an “industry-wide evaluation” by the FDA of drugs that do not meet the post-marketing checkpoints on which their accelerated nods were based, the company said Monday.

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Bob Nelsen (Photo by Michael Kovac/Getty Images)

With stars aligned and cash in re­serve, Bob Nelsen's Re­silience plans a makeover at 2 new fa­cil­i­ty ad­di­tions to its drug man­u­fac­tur­ing up­start

Bob Nelsen’s new, state-of-the-art drug manufacturing initiative is taking shape.

Just 3 months after gathering $800 million of launch money, a dream team board and a plan to shake up a field where he found too many bottlenecks and inefficiencies for the era of Covid-19, Resilience has snapped up a pair of facilities now in line for a retooling.

The company has acquired a 310,000-square-foot plant in Boston from Sanofi along with a 136,000-square-foot plant in Ontario to add to a network which CEO Rahul Singhvi says is just getting started on building his company’s operations up. The Sanofi deal comes with a contract to continue manufacturing one of its drugs.

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Af­ter bail­ing on Covid-19 vac­cines, Mer­ck will team up with J&J to pro­duce its shot as part of un­usu­al Big Phar­ma pact

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President Joe Biden on Tuesday is expected to announce a partnership between drugmakers Merck and Johnson & Johnson to jointly produce J&J’s recombinant protein Covid-19 vaccine that received the FDA’s emergency use authorization Saturday, the Washington Post reported.

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AbbVie has teed up a small but intriguing biotech buyout after looking over the preclinical work it’s been doing in Parkinson’s disease.

The company is called Mitokinin, a Bay Area biotech spun out of the lab of UCSF’s Kevan Shokat, whose scientific explorations have formed the academic basis of a slew of startups in the biotech hub. One of Shokat’s PhD students in the lab, Nicholas Hertz, co-founded Mitokinin using their lab work on PINK1 suggesting that amping up its activity could play an important role in regulating the mitochondrial dysfunction contributing to Parkinson’s disease pathogenesis and progression.

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“I just want to be laser-focused on getting to that point,” Sekhri says, before acknowledging, “Yes, it absolutely crossed my mind.”

Sekhri, a longtime biopharma executive with tenures at Sanofi and Novartis, is now entering year three as CEO of eGenesis, the biotech that George Church protégé Luhan Yang founded to genetically alter pigs so that they can be used for organ transplants. He led them through one megaround and has just closed another, raising $125 million from 17 different investors to push the first-ever (humanized) pig to human transplants into the clinic.

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FibroGen will likely have to delay its US rollout for roxadustat once again.

In an unexpected move, the FDA is convening its Cardiovascular and Renal Drugs Advisory Committee to review the NDA in an advisory committee meeting. The date is yet to be confirmed.

Just a few weeks ago, SVB Leerink analyst Geoffrey Porges predicted that the roxa approval could come ahead of the PDUFA date on March 20 — effusive despite already being let down once by the FDA’s extension of its review back in December. AstraZeneca, which is partnered with FibroGen on the chronic kidney disease-related anemia drug, disclosed regulators had requested further clarifying analyses of clinical data.

In­tro­duc­ing End­pointsF­DA+, our new pre­mi­um week­ly reg­u­la­to­ry news re­port led by Zachary Bren­nan

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Coverage will be led by our new senior editor, Zachary Brennan. He joins Endpoints from POLITICO, where he covered pharma. Prior to that he was the managing editor for Regulatory Focus, a news publication from the Regulatory Affairs Professionals Society.

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All the pieces needed to trigger a third wave of Covid-19 vaccine supply to start washing over the US fell neatly into place over the weekend.

After providing for a brief mime of regulatory judiciousness, the FDA stamped their emergency approval on J&J’s Covid-19 vaccine Saturday, adding to the Biden administration’s plan aimed at ending the pandemic in the near term — at least in the US. The CDC came through on Sunday with its stamp of approval and J&J is reportedly expected to start delivering vaccine sometime in the next few days.

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The fu­ture of mR­NA, J&J's vac­cine ad­comm, Mer­ck­'s $1.85B au­toim­mune bet and more

Welcome to the third installment of Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

If this report was helpful in recapping it all for you, please do share it with your colleagues.

Get ready for FDA’s third Covid-19 vaccine

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