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.

The 20 un­der 40: In­side the next gen­er­a­tion of bio­phar­ma lead­ers

“Each generation needs a new music,” Francis Crick wrote in 1988, reflecting back on his landmark discovery. Crick was 35, then, in 1953, when he began working with a 23-year-old named James Watson, and 37 when the pair unveiled the double helix. Rosalind Franklin, whose diffraction work undergirded their metal model, was 32.

The model would become the score for a new era in biology, one devoted to cracking the basic structures turning inside life. Subsequent years would bring new conductors and new rhythms: Robert Swanson, 29 when he convinced a 39-year-old Herb Boyer to build a company off his work and call it Genentech; Phillip Sharp, 29 when he discovered RNA splicing and 34 when he co-founded Biogen; Frances Arnold, 36 when she pioneered directed evolution; Feng Zhang, 31 when he published his CRISPR paper.

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Chart-top­ping ven­ture cash? Strong deal flow? In the month Covid-19 ripped around the globe? Yup

It turns out that even sending everyone from the CEO to rank-and-file staffers home to work in the middle of a Category 5 pandemic wasn’t enough to put a crimp in the flow of venture cash into biopharma. And even dealmaking held its own against the howling winds of misfortune — largely because a group of savvy players was quick to adjust to the new reality.

Our deal expert Chris Dokomajilar ran the numbers for us on a month-to-month basis and found that not only was venture money flowing during the panicky month of March, but it was also hitting home in record sums compared to the last 26 months of deal flow.

Say what?

As you can see in the top chart below, Dokomajilar outlined how the industry racked up $2.41 billion in total for March, just barely ahead of one other topper during the heady days of August 2018.

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FDA Commissioner Stephen Hahn and President Donald Trump at a press briefing on March 19, 2020. (AP Images)

Biotech ex­ecs warn that the FDA is fum­bling their re­sponse to the Covid-19 open-door promise, de­lay­ing progress

A few days ago the FDA touted a procedure for Covid-19 meds that committed the agency to immediate action for developers, formalizing a high-speed response that’s been promised for weeks.

Bioregnum Opinion Column by John Carroll

Decisions that once required months would be measured in hours under the Coronavirus Treatment Acceleration Program. “In many cases” trial protocols could be hammered out in less than a single day. If you had a potential solution to the crisis, the appropriate staffer would be in touch “to get studies underway quickly.”

It would be the ultimate high-speed regulatory pathway from Phase I to approval. Red tape was banished.

But it’s clear that for some — and quite likely many — biopharma execs, the actual agency response has not measured up to the promise. Beyond the front ranks of advanced companies in the field, like Gilead, or for drugs endorsed by President Trump, it may not even come close.

“The first response is this form letter everyone gets,” says one biotech CEO who’s reached out to the FDA on Covid-19. And when you try to cut through that, the ball gets dropped as it is passed from top officials to the frontline staff actually charged with getting things done.

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GSK's Hal Bar­ron buys a $250M stake in George Scan­gos' Vir and makes a bee­line to the clin­ic with Covid-19 an­ti­bod­ies

GlaxoSmithKline is diving straight into the swirling waters of Covid-19 R&D work, and investing $250 million to grab a chunk of equity in one of the emerging stars in infectious disease research to make it official.

GSK put out word this morning that it is partnering with Vir Biotechnology $VIR, the infectious disease startup founded in the Bay Area by former Biogen CEO George Scangos. They’re planning a leap into Phase II studies for 2 preclinical antibody candidates — VIR-7831 and VIR-7832 — that have been engineered to target the SARS-CoV-2 spike protein.

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UP­DAT­ED: A small, ob­scure biotech just won big with their IPO. In this mar­ket. Are you kid­ding me?

How could a small, largely unknown biotech that emerged from stealth mode just months ago with early-stage cancer programs jump onto Wall Street in the middle of a Category 6 financial hurricane and sail through with a $165 million IPO?

And what does that mean for the rest of the industry waiting to see just how much damage global lockdowns will wreak on clinical development?

The biotech is a company called Zentalis. The crew there nabbed an $85 million crossover round late last year — notably waiting 5 years before waving the numbers around to attract attention, according to my read of a FierceBiotech story. Perceptive joined in, but the syndicate was not in general the kind of marquee affair that gets tongues wagging.

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Ready to de­clare a de­fin­i­tive come­back in two months, Im­munomedics stops PhI­II ear­ly, re­cruits new CEO

More than a year ago, hit by a surprise complete response letter from the FDA, Immunomedics bid its then-CEO, Michael Pehl, adieu and began a 15-month quest to resolve the manufacturing issues cited in the CRL and seek a new leader — all the while moving forward with a Phase III study on its lead drug for metastatic triple-negative breast cancer.

Today the biotech said their stars are finally aligning. Not only is Novartis Oncology vet Harout Semerjian coming on board as CEO to steer what they believe will be a smooth sail to a new PDUFA date in June, Immunomedics has also been informed that their late-stage trial can be stopped early due to “compelling evidence of efficacy.”

An­oth­er day, an­oth­er boat­load for biotech. Deer­field adds $840M to rush of ven­ture dol­lars

The biotech dollars just keep rolling in.

Even as the world economy faces an economic contraction unprecedented in nature, biotech venture capital firms are announcing huge new investment pots. The latest? Deerfield Management Co.

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Small mol­e­cules, bi­o­log­ics and now gene ther­a­pies: Ger­many's Evotec adds an­oth­er feath­er to its R&D cap

German drug discovery company Evotec — which has a thriving rolodex of biopharma partners such as Bayer, Boehringer Ingelheim, Novartis, Novo Nordisk, Pfizer, Sanofi, and Takeda — is now venturing into gene therapies.

The company swallowed Seattle-based Just Biotherapeutics, a company focused on reducing the cost of manufacturing protein therapies last year. It is now setting up a dedicated R&D site for gene therapies in Austria, in an effort to achieve a “modality-agnostic” repertoire — small molecules, biologics and now gene therapies.

A pair of PhI­II fail­ures spells last rites for Men­lo’s once-promis­ing Mer­ck drug

Four months after an intercontinental merger, Menlo Therapeutics is counting yet another pair of trial failures — ones with significant consequences for the companies, their shareholders and the drug.

In two pivotal Phase III trials, Menlo’s lead drug serlopitant failed to treat pruritus associated with prurigo nodularis — basically itchiness from a particular skin disease that causes red lesions on a person’s arms or legs. Serlopitant has long been the company’s only drug and as recently as 2018, it looked promising enough to support a stock price of $37. In April of that year, a Phase II failure demolished the stock price overnight: $35 to $9. Other subsequent stumbles trickled the ticker down to just above $2.