Avro­bio re­tools Fab­ry gene ther­a­py plans af­ter com­pet­ing drug's full ap­proval shuts path­way to an ac­cel­er­at­ed nod

It’s been a long road for lentivi­ral gene ther­a­py play­er Avro­bio in the rare lyso­so­mal dis­or­der Fab­ry dis­ease af­ter ear­ly da­ta sent in­vestors run­ning for the hills back in 2018. Right on the heels of a promis­ing read­out, Avro­bio will now tin­ker with its reg­u­la­to­ry plans for that ther­a­py af­ter the FDA flipped the script and hand­ed a com­pet­ing drug an un­like­ly full ap­proval.

The biotech will re­jig­ger its de­vel­op­ment plans for AVR-RD-01, an in­ves­ti­ga­tion­al gene ther­a­py for Fab­ry dis­ease, af­ter the FDA grant­ed a full ap­proval to Sanofi’s en­zyme re­place­ment ther­a­py Fab­razyme back in March, val­i­dat­ing a new kid­ney biop­sy sur­ro­gate end­point Avro­bio now hopes to pur­sue, the com­pa­ny said Mon­day.

Avro­bio was in talks with the FDA to pur­sue an ac­cel­er­at­ed ap­proval for AVR-RD-01 based on kid­ney sub­strate re­duc­tion with a con­fir­ma­to­ry study to fol­low. Af­ter it sub­mit­ted its brief­ing book to the FDA, the agency hand­ed Fab­razyme a full ap­proval — 18 years af­ter it first re­ceived an ac­cel­er­at­ed nod based on the re­duc­tion of the lipid Gb3.

That ap­proval marked a new path for­ward for ERTs, which are used as the stan­dard of care in Fab­ry dis­ease, to re­ceive full nods, but forced Avro­bio to fo­cus on a head-to-head reg­is­tra­tional study against Fab­razyme, and shut off its hopes for an ac­cel­er­at­ed OK. Avro­bio will still go ahead on ex­pand­ing its Phase II study, which has dosed six pa­tients so far and has seen im­prove­ment on end­points “sim­i­lar” to Gb3 re­duc­tion, with hopes of con­vinc­ing the FDA to move ahead on a Phase III reg­is­tra­tional study pegged for the mid­dle of next year.

But noth­ing’s cer­tain for Avro­bio, and it warned that one ther­a­py’s ac­cept­ed sur­ro­gate end­point doesn’t nec­es­sar­i­ly trans­late to an­oth­er. The ex vi­vo ther­a­py us­es pa­tient’s en­gi­neered hematopoi­et­ic stem cells to re­place pa­tients’ func­tion­al en­zymes used to break down Gb3.

Ge­off MacK­ay

Start­ing this quar­ter, Avro­bio in­tends to ex­pand en­roll­ment in its Phase II FAB-GT study to in­clude fe­male par­tic­i­pants and pa­tients re­gard­less of an­ti­body-sta­tus ex­clu­sions with the goal of hit­ting 14 pa­tients to­tal. Mean­while, in­ves­ti­ga­tors will al­so mon­i­tor a new set of bio­mark­er end­points in­tend­ed to high­light ERTs’ short­com­ings, in­clud­ing po­ten­tial for AVR-RD-01 “to ad­dress car­dio­vas­cu­lar and cen­tral ner­vous sys­tem man­i­fes­ta­tions,” the com­pa­ny said.

It’s an un­wel­come turn of events for Avro­bio af­ter it re­vealed tri­umphant Phase II fol­low-up da­ta in Feb­ru­ary show­ing a 100% re­duc­tion in kid­ney sub­strate lev­els af­ter one year in a sin­gle pa­tient dosed with the com­mer­cial form of AVR-RD-01. It was a small but promis­ing win­dow in­to the pos­si­bil­i­ty of a rel­a­tive­ly quick path to mar­ket, which could now be pushed back con­sid­er­ably.

Ear­ly da­ta for AVR-RD-01 left a bad taste in in­vestors’ mouths af­ter the ther­a­py showed ef­fi­ca­cy in Fab­ry in late 2018 but al­so post­ed low vec­tor copy num­bers, an in­di­ca­tor of how long the ther­a­py hangs around in the body. CEO Ge­off MacK­ay at the time ar­gued those da­ta were in line with ex­pec­ta­tions for how the ex vi­vo ther­a­py was de­signed to work, but in­vestors fled in droves all the same. Mean­while, the com­pa­ny tout­ed da­ta show­ing three of five pa­tients in a Phase I test had moved off ERTs for their dis­ease.

Ed­i­tor’s Note: This sto­ry has been up­dat­ed to clar­i­fy the pri­ma­ry end­point in Avro­bio’s Phase II study for AVR-RD-01.

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His­toric drug pric­ing re­forms pass; Pfiz­er ac­quires GBT; The long search for non-opi­oid pain drugs; 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.

The Endpoints Weekly has officially crossed the 60,000 mark on subscribers — thanks to all of your support. As the editorial team grows, we’ve been able to do a lot more, with many of those on display this week. Be sure to check out Lei Lei Wu’s deep dive on pain R&D. If you missed it, you may also rewatch her companion panel here.

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Gold for adults, sil­ver for in­fants: Pfiz­er's Pre­vnar 2.0 head­ed to FDA months af­ter Mer­ck­'s green light

Pfizer was first to the finish line for the next-gen pneumococcal vaccine in adults, but Merck beat its rival with a jab for children in June.

Now, two months after Merck’s 15-valent Vaxneuvance won the FDA stamp of approval for kids, Pfizer is out with some late-stage data on its 20-valent shot for infants.

Known as Prevnar 20 for adults, Pfizer’s 20vPnC will head to the FDA by the end of this year for an approval request in infants, the Big Pharma said Friday morning. Discussions with the FDA will occur first and more late-stage pediatric trials are expected to read out soon, informing the regulatory pathway in other countries and regions.

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Seagen interim CEO Roger Dansey and Daiichi Sankyo CEO Sunao Manabe

Paving the way for Mer­ck­'s buy­out, Seagen los­es ar­bi­tra­tion dis­pute with Dai­ichi over ADC tech

As Seagen awaits a final buyout offer from Merck that could be in the territory of $40 billion, Seagen revealed Friday afternoon that it lost an arbitration dispute with Daiichi Sankyo relating to the companies’ 2008 collaboration around the use of antibody-drug conjugate (ADC) technology.

But that loss likely won’t matter much when it comes to Merck’s deal.

After breaking off its pact with Daiichi in mid-2015, the two companies battled over “linker” tech — a chemical bridge between an ADC’s antibody component and the cytotoxic payload — that Seagen claims Daiichi would improve upon and implement in its current generation of ADCs.

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Benjamin Oakes, Scribe Therapeutics CEO

CEO of Doud­na spin­out: With­in five years, genome ed­i­tors will have a 're­al­ly big im­pact' on pa­tients' lives

“CRISPR-by-design” is the idea behind Scribe Therapeutics, a company spun out from Jennifer Doudna’s Nobel-winning lab that’s competing in a closely-tracked field of genome editor companies just starting to make their way to the clinic.

After nabbing $100 million last March for its Series B funding round, Scribe is taking a different tack from some of its competitors, crafting a new enzyme isolated from bacteria called CasX, which has now been tweaked extensively and may be targeted to a range of genome-related diseases, offering a plethora of therapeutic options.

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House pass­es his­toric drug pric­ing re­forms, lin­ing up decades-in-the-mak­ing win for Biden and De­moc­rats

The US House of Representatives today voted along party lines (all Dems voted for it), 220-207 to pass new, wide-ranging legislation that will allow Medicare drug price negotiations for the first time ever, and cap seniors’ drug expenses to $2,000 per year and seniors’ insulin costs at $35 per month.

Setting up a major victory for President Joe Biden, representatives returned from their summer recess to pass the Inflation Reduction Act, even as many noted the bill would only modestly reduce inflation.

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Senate Finance Committee Chair Ron Wyden (D-OR) (Francis Chung/E&E News/POLITICO via AP Images)

Sen­ate Fi­nance chair con­tin­ues his in­ves­ti­ga­tion in­to phar­ma tax­es with re­quests for Am­gen

Amgen is the latest pharma company to appear on the radar of Senate Finance Committee Chair Ron Wyden (D-OR), who is investigating the way pharma companies are using subsidiaries in low- or zero-tax countries to lower their tax bills.

Like its peers Merck, AbbVie and Bristol Myers Squibb, Wyden notes how Amgen uses its Puerto Rico operations to consistently pay tax rates that are substantially lower than the U.S. corporate tax rate of 21%, with an effective tax rate of 10.7% in 2020 and 12.1% in 2021.

FDA ap­proves sec­ond in­di­ca­tion for As­traZeneca and Dai­ichi's En­her­tu in less than a week

AstraZeneca and Daiichi Sankyo’s antibody-drug conjugate Enhertu scored its second approval in less than a week, this time for a subset of lung cancer patients.

Enhertu received accelerated approval on Thursday to treat adults with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, and who have already received a prior systemic therapy.

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J&J to re­move talc prod­ucts from shelves world­wide, re­plac­ing with corn­starch-based port­fo­lio

After controversially spinning out its talc liabilities and filing for bankruptcy in an attempt to settle 38,000 lawsuits, Johnson & Johnson is now changing up the formula for its baby powder products.

J&J is beginning the transition to an all cornstarch-based baby powder portfolio, the pharma giant announced on Thursday — just months after a federal judge ruled in favor of its “Texas two-step” bankruptcy to settle allegations that its talc products contained asbestos and caused cancer. An appeals court has since agreed to revisit that case.