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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End­points 20(+2) un­der 40, 2023; Bio­phar­ma's high­est-paid CEOs; N-of-1 CRISPR sto­ry goes on af­ter tragedy; and more

Welcome back to 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.

We will be off Monday in observance of Memorial Day — and when we get back, it will be a straight march to ASCO, BIO and more. Enjoy the (long) weekend!

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Rich Horgan (R) with his late brother, Terry

Rich Hor­gan spear­head­ed a gene ther­a­py for his broth­er. The tri­al end­ed in tragedy, but the work con­tin­ues for more pa­tients

Rich Horgan’s quest to create a custom gene therapy for his brother, Terry, ended in tragedy. But Horgan doesn’t believe it’s the end of the story.

Terry, a 27-year-old patient with Duchenne muscular dystrophy, died last October just eight days after receiving the therapy in a clinical trial in which he was the only participant. The case raised questions about the safety of certain gene therapies and what would happen to other drug programs under a nonprofit that Horgan created, called Cure Rare Disease.

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Bio­phar­ma's 20 high­est-paid CEOs of 2022, each bring­ing in $20M+ pay­days

Even in a down year for much of the biopharma market, 20 CEOs brought in pay packages valued at more than $20 million, an Endpoints News analysis found.

Endpoints collected data on more than 350 CEO compensation packages, covering a wide range of pharma, biotech, and life sciences companies. All told, the 20 largest earners made over $725 million in 2022 — an average package of $36.4 million. Three brought in paydays over $50 million, and one CEO broke the $100 million mark.

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Douglas Love, Annexon CEO

An­nex­on’s GA drug miss­es on pri­ma­ry goal but win on vi­su­al acu­ity will be fo­cus of planned late-stage tri­al

Annexon’s complement inhibitor didn’t prove better than sham at reducing lesion growth in a leading cause of blindness, but the biotech still plans to move forward on the back of secondary endpoints showing visual acuity preservation, which will “certainly” be the primary goal in a late-stage trial to be discussed shortly with the FDA, CEO Douglas Love told Endpoints News. 

The California biotech’s ANX007 was not statistically significant compared to pooled sham, the comparator, at 12 months in patients with geographic atrophy, per a Wednesday presentation. In every-month dosing, the GA lesion area changed about 6.2% from baseline (p=0.526) and 1.3% (p=0.896) in the every-other-month group. In a March note, Jefferies analyst Suji Jeong said a reduction of 20% to 30% would be “encouraging.”

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The 20(+2) un­der 40: Your guide to the next gen­er­a­tion of biotech lead­ers

This year’s list of 20 biotech leaders under the age of 40 includes a huge range of ambitions. Some of our honorees are planning to create the next big drug giant. Others are pushing the bounds of AI. One is working to revolutionize TB testing. All are compelling talents who are still young in age, but already far along in achievement.

And, as in years past, we went over. The 20 are actually 22 because of two double profiles that reflect how important teamwork is in the industry. As one of our honorees, Joe Illingworth of DJS Antibodies, told me in our interview, “It takes a village to raise a biotech.”

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FDA ap­proves Lex­i­con’s heart-fail­ure drug af­ter de­feat in di­a­betes

The FDA on Friday approved Lexicon’s heart failure drug sotagliflozin following a string of setbacks for the pharma company, including an FDA rejection in diabetes and the loss of a development deal with Sanofi.

The dual SGLT1 and SGLT2 inhibitor will be marketed as Inpefa and is a once-daily tablet. It’s been approved to reduce the risk of cardiovascular death and heart failure-related hospitalization or urgent visits in adults with heart failure or type 2 diabetes mellitus, chronic kidney disease, and other cardiovascular risk factors. The label spans the range of left ventricular ejection fraction, including preserved ejection fraction and reduced ejection fraction, as well as patients with or without diabetes, Lexicon said Friday.

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Eu­ro­pean Com­mis­sion to re­ceive few­er Pfiz­er-BioN­Tech vac­cine dos­es un­der amend­ed con­tract

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The Commission previously struck a contract in May 2021 for 900 million doses, with the option to purchase another 900 million. Of those, 450 million were expected to be delivered in 2023, though an amendment now calls for fewer doses. While neither the Commission nor Pfizer and BioNTech have revealed an exact amount, an unnamed source told Reuters that the amendment reduces the remaining expected doses by about a third.

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Teresa Bitetti, Takeda's president of the global oncology business unit

Take­da wins pri­or­i­ty re­view for $400M col­orec­tal can­cer drug, li­censed from Hutchmed in Jan­u­ary

Takeda and Hutchmed scored a priority review Thursday afternoon for a colorectal cancer drug, the companies announced.

The experimental drug in question is fruquintinib, previously approved in China in 2018 to treat metastatic colorectal cancer. Takeda and Hutchmed are aiming to bring fruquintinib to the US and other countries outside China in the same indication, and the FDA set its decision date for Nov. 30 of this year.

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