Geoff McDonough, CEO (Generation Bio)

Gen­er­a­tion Bio snaps up Boston area plant as it rolls out a man­u­fac­tur­ing process it thinks will be a game chang­er

Gen­er­a­tion Bio is look­ing to move the field of gene ther­a­py in­to the fu­ture, and thinks it has a man­u­fac­tur­ing process in place that will al­low enough scale for broad dis­ease in­di­ca­tions. Now, all it needs is a plant to put those large-scale am­bi­tions in­to ac­tion.

Gen­er­a­tion signed a lease on a new 104,000-square-foot fa­cil­i­ty in Waltham, MA, set to be­come op­er­a­tional in 2023. The fa­cil­i­ty will be avail­able for pre­clin­i­cal and clin­i­cal de­vel­op­ment for its lead he­mo­phil­ia A pro­gram.

The shell is set up, and it has all the ad­van­tages that come with a large, in­dus­tri­al site that doesn’t al­ways fit in­side the crowd­ed in­fra­struc­ture of Cam­bridge, the fifth most dense­ly pop­u­lat­ed city in the US. But the Waltham site is just eight miles away from Gen­er­a­tion’s Kendall Square head­quar­ters, and the abil­i­ty to pro­vide greater con­nec­tiv­i­ty be­tween the two sites was im­por­tant to the team as it rolls out a brand-new man­u­fac­tur­ing process.

The lease will cost $104 mil­lion over a 12-year pe­ri­od, and Gen­er­a­tion will in­vest $45 mil­lion over the next two years in­to the site. The team will still use CD­MOs be­fore and af­ter the site is up and run­ning to en­sure re­dun­dan­cy and se­cure ad­di­tion­al ccD­NA sup­ply, but CEO Ge­off Mc­Do­nough said the team wants to re­ly on greater flex­i­bil­i­ty and greater fi­nan­cial lever­age that comes with its own sup­ply chain in house.

The holdup sur­round­ing tra­di­tion­al man­u­fac­tur­ing is scale. For ex­am­ple: there are 200 mil­lion peo­ple world­wide with he­mo­phil­ia A. “You just don’t have enough scale to get to (them),” Mc­Do­nough said. “This move al­lows us to con­sid­er ad­dress­ing those very large pop­u­la­tions.”

Gen­er­a­tion Bio is tout­ing what it’s call­ing a game-chang­ing man­u­fac­tur­ing process called rapid en­zy­mat­ic syn­the­sis — oth­er­wise known as RES — that can speed clin­i­cal man­u­fac­tur­ing of its non-vi­ral gene ther­a­pies from 28 days down to one.

With more flex­i­bil­i­ty on its man­u­fac­tur­ing runs, Gen­er­a­tion’s team is tar­get­ing in­fec­tious dis­eases and oth­er larg­er in­di­ca­tions, in ad­di­tion to its cur­rent work in rare ge­net­ic dis­eases. The com­pa­ny has been work­ing on two lead pro­grams for he­mo­phil­ia A and phenylke­tonuria (PKU). Wil­son dis­ease and Gauch­er dis­ease are al­so on the list

“For first gen­er­a­tion AAV man­u­fac­tur­ing, mak­ing that con­struct can on­ly be done in a cell sys­tem,” Mc­Do­nough said in a call with End­points News Tues­day. “Since you’re mak­ing it with cap­sid, you’re lim­it­ing your­self to a few thou­sand liters of prod­uct, and with that, very few pa­tients you can help, some­where around 10,000. We’ve al­ways had this idea of ‘look, our drug sub­stance is DNA, there are oth­er ways to make DNA in­clud­ing en­zy­mat­i­cal­ly, where you take the plas­mid in, and you un­der­go a fi­nite set of en­zy­mat­ic trans­for­ma­tions, and then you get that drug sub­stance, which is closed end­ed DNA com­ing out.”

ZS Per­spec­tive: 3 Pre­dic­tions on the Fu­ture of Cell & Gene Ther­a­pies

The field of cell and gene therapies (C&GTs) has seen a renaissance, with first generation commercial therapies such as Kymriah, Yescarta, and Luxturna laying the groundwork for an incoming wave of potentially transformative C&GTs that aim to address diverse disease areas. With this renaissance comes several potential opportunities, of which we discuss three predictions below.

Allogenic Natural Killer (NK) Cells have the potential to displace current Cell Therapies in oncology if proven durable.

Despite being early in development, Allogenic NKs are proving to be an attractive new treatment paradigm in oncology. The question of durability of response with allogenic therapies is still an unknown. Fate Therapeutics’ recent phase 1 data for FT516 showed relatively quicker relapses vs already approved autologous CAR-Ts. However, other manufacturers, like Allogene for their allogenic CAR-T therapy ALLO-501A, are exploring novel lymphodepletion approaches to improve persistence of allogenic cells. Nevertheless, allogenic NKs demonstrate a strong value proposition relative to their T cell counterparts due to comparable response rates (so far) combined with the added advantage of a significantly safer AE profile. Specifically, little to no risk of graft versus host disease (GvHD), cytotoxic release syndrome (CRS), and neurotoxicity (NT) have been seen so far with allogenic NK cells (Fig. 1). In addition, being able to harness an allogenic cell source gives way to operational advantages as “off-the-shelf” products provide improved turnaround time (TAT), scalability, and potentially reduced cost. NKs are currently in development for a variety of overlapping hematological indications with chimeric antigen receptor T cells (CAR-Ts) today, and the question remains to what extent they will disrupt the current cell therapy landscape. Click for more details.

What lured Hal Bar­ron away?; Top FDA minds on ac­cel­er­at­ed ap­proval re­forms; ‘Dead wrong’ Aduhelm ad blitz; 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.

Nothing can really compete with Hal Barron’s departure from GlaxoSmithKline as the news of the week, but we do have plenty of original reporting and analysis from the Endpoints team in this edition. Enjoy and have a nice weekend.

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Mer­ck wins le­gal bat­tle over in­sur­ance cov­er­age af­ter ran­somware at­tack

Merck has emerged victorious from a years-long legal battle with insurers over the coverage of more than a billion dollars in losses from the malware NotPetya, with a New Jersey Superior Court judge concluding that the responsibility is on insurers to clarify their policies around cyber attacks.

The pharma giant was one of several victims of a global cyber attack back in 2017 that also hit Danish shipping company Maersk, American food company Mondelēz, French construction giant Saint-Gobain and even the systems monitoring the Chernobyl nuclear power stations, Bloomberg reported back in 2019.

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A Sen­ate bill wants to even an 'un­lev­el play­ing field' for do­mes­tic, for­eign in­spec­tion drop-ins amid back­log

Amid geopolitical tensions between the US and China, two Republican senators are calling for a bill that would aim to strike a balance on domestic and foreign inspection requirements from the FDA.

Sens. Mike Braun (R-IN) and Joni Ernst (R-IA) have penned a bill called the Creating Efficiency in Foreign Inspections Act. It contains a bit of rhetoric, highlighting “communist China” not once, but twice in the release, but states that the goal is to even the playing field between foreign and American manufacturers.

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Man­u­fac­tur­ing woes con­tin­ue for Au­robindo af­ter FDA's warn­ing let­ter

An active pharmaceutical ingredient site in India has been handed a warning letter from the FDA, following an August 2021 inspection.

AuroLife Pharma’s Hyderabad site, which is part of the Aurobindo group of companies, was handed the letter in November. It’s the latest in a string of manufacturing woes the company has battled as of late.

Unit 1 of its Hyderabad site was inspected, and received an official action initiated notice from the FDA. “The company believes that this will not impact the existing business from this facility,” it said in a filing.

Crit­ics push back on Alzheimer’s As­so­ci­a­tion ad blitz to get Medicare to change its Aduhelm rul­ing: 'Dead wrong'

The latest Alzheimer’s Association advertising campaign encourages people to fight.

Not against the disease or for more research or treatments, but against the Centers for Medicare and Medicaid Services. More specifically, CMS’ recent reimbursement decision to only pay for Biogen and Eisai’s controversial Alzheimer’s drug Aduhelm for patients in clinical trials.

With CMS’ preliminary decision now in a 30-day comment period, patient advocates’ goal is to convince CMS to reverse its decision with a marketing blitz and public pressure.

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Dan O'Day, Gilead CEO (Jim Watson/AFP via Getty Images)

Fail­ing to con­firm clin­i­cal ben­e­fit, Gilead pulls 2 ac­cel­er­at­ed ap­proval in­di­ca­tions for can­cer drug

Gilead recently decided to pull two indications for its cancer drug Zydelig — in relapsed follicular B-cell non-Hodgkin lymphoma (FL) and relapsed small lymphocytic leukemia (SLL) — after failing to complete the confirmatory trials required as part of the accelerated approvals from 2014.

“As the treatment landscape for FL and SLL has evolved, enrollment into the confirmatory study has been an ongoing challenge,” Gilead said in a statement, noting it formally notified the FDA of its decision to voluntarily withdraw these indications.

Richard Pazdur (via AACR)

Time lim­its on ac­cel­er­at­ed ap­provals? FDA's on­col­o­gy chief Rick Paz­dur eyes po­ten­tial re­forms via in­ter­na­tion­al ap­proach­es

The spotlight on the accelerated approval pathway continues to shine bright, with the FDA’s top oncology official writing in an opinion that the pathway may be strengthened with bits and pieces of what other regulators in Europe and elsewhere have done with their expedited approval pathways, such as adding expiration dates for these faster approvals to ensure they confirm clinical benefit in a timely manner.

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Hal Barron, Endpoints UKBIO20 (Jeff Rumans)

'Al­tos was re­al­ly a once-in-a-life­time op­por­tu­ni­ty': Hal Bar­ron re­flects on his big move

By all accounts, Hal Barron had one of the best jobs in Big Pharma R&D. He made more than $11 million in 2020, once again reaping more than his boss, Emma Walmsley, who always championed him at every opportunity. And he oversaw a global R&D effort that struck a variety of big-dollar deals for oncology, neurodegeneration and more.

Sure, the critics never let up about what they saw as a rather uninspiring late-stage pipeline, where the rubber hits the road in the Big Pharma world’s hunt for the next big near-term blockbuster, but the in-house reviews were stellar. And Barron was firmly focused on bringing up the success rate in clinical trials, holding out for the big rewards of moving the dial from an average 10% success rate to 20%.

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