CPhI: As Covid-19 re­stric­tions ease, an in­spec­tion back­log could have a big ef­fect on new drugs, gener­ics

Like the me­chan­ics in a clock, phar­ma man­u­fac­tur­ing of­ten qui­et­ly ticks away un­til one piece of the ma­chine hits a snag. Now, as part of its an­nu­al check-in on the in­dus­try, CPhI is high­light­ing a grow­ing back­log of man­u­fac­tur­ing in­spec­tions for­eign and do­mes­tic to the US as a po­ten­tial­ly ma­jor snag in the gears.

To bat­tle sup­ply chain is­sues, the US has en­cour­aged an in­crease in do­mes­tic pro­duc­tion, which has not been easy or con­sis­tent. Nielsen Hobbs, In­for­ma Phar­ma In­tel­li­gence’s ex­ec­u­tive ed­i­tor of US pol­i­cy and reg­u­la­tion, says the biggest chal­lenge fac­ing man­u­fac­tur­ers go­ing for­ward could be in­spec­tions from reg­u­la­tors. A hia­tus has last­ed over a year, as trav­el has been re­strict­ed, but that is over­due to end.

“How well have we main­tained what we need to keep,” Hobbs says in the re­port. “And how well po­si­tioned are we to make things bet­ter?”

The in­dus­try has bat­tled wide­spread ni­trosamine con­t­a­m­i­na­tion in the past year. Pfiz­er was forced to re­call all lots of its .5 mg and 1 mg tablets of the an­ti-smok­ing drug Chan­tix at the end of Sep­tem­ber, af­ter ini­tial­ly re­call­ing four lots in June, and al­low­ing man­u­fac­tur­ers to dis­trib­ute batch­es so long as the lev­el of ni­trosamines were be­low the ac­cept­able lim­it.

But that prob­lem goes deep­er than Pfiz­er. Last year, the FDA found high lev­els of ND­MA in some ver­sions of gener­ic di­a­betes drug met­formin. Be­fore Pfiz­er, Viona Phar­ma­ceu­ti­cals is­sued a re­call for two lots of its 750 mg ex­tend­ed-re­lease met­formin tablets, and since No­vem­ber 2020, there have been two more drugs re­called be­cause of re­ports of ND­MA. In 2018, drug pres­sure drug val­sar­tan was pulled for the same rea­son.

The im­pu­ri­ties could in­crease a cus­tomer’s risk of can­cer if they are ex­posed to them over a long pe­ri­od of time.

“As the ni­trosamine is­sue un­folds, in­dus­try is find­ing it ter­ri­bly dif­fi­cult to as­sess and man­age the risks,” Hobbs said. “On the bright side, there could be learn­ings on how to es­tab­lish spec­i­fi­ca­tions that are tru­ly pa­tient rel­e­vant, which could free the in­dus­try from qual­i­ty thresh­olds that grow even tighter as an­a­lyt­i­cal meth­ods be­come in­creas­ing­ly dis­cern­ing.”

But as ni­trosamine is­sues con­tin­ue on, the FDA will be forced to over­come a mas­sive back­log of do­mes­tic and for­eign in­spec­tions that have not on­ly cast doubt on the qual­i­ty of drugs and API im­port­ed in­to the US but al­so have pushed off drug­mak­ers ap­pli­ca­tions for mar­ket­ing ap­proval.

In a June re­port to Con­gress, the FDA not­ed that more than 8,000 in­spec­tions had been de­layed in 2020 alone with thou­sands more stack­ing up in 2021. De­spite the agency now hit­ting its stride, those de­lays have pushed off new drug ap­provals and in­spec­tions not con­sid­ered “mis­sion crit­i­cal” by the agency and leav­ing the en­tire in­dus­try won­der­ing whether their set-up­on dates will be hon­ored.

There are a num­ber of po­ten­tial so­lu­tions for that ques­tion that have been in the works for years, in­clud­ing re­mote in­spec­tions, but the FDA has on­ly rolled those func­tions out in a lim­it­ed ca­pac­i­ty. That means that a back­log could have a big ef­fect on the in­dus­try for years to come.

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.

Graphic: Kathy Wong for Endpoints News

What kind of biotech start­up wins a $3B syn­di­cate, woos a gallery of mar­quee sci­en­tists and re­cruits GSK's Hal Bar­ron as CEO in a stun­ner? Let Rick Klaus­ner ex­plain

It started with a question about a lifetime’s dream on a walk with tech investor Yuri Milner.

At the beginning of the great pandemic, former NCI chief and inveterate biotech entrepreneur Rick Klausner and the Facebook billionaire would traipse Los Altos Hills in Silicon Valley Saturday mornings and talk about ideas.

Milner’s question on one of those mornings on foot: “What do you want to do?”

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FDA+ roundup: FDA's neu­ro­science deputy de­parts amid on­go­ing Aduhelm in­ves­ti­ga­tions; Califf on the ropes?

Amid increased scrutiny into the close ties between FDA and Biogen prior to the controversial accelerated approval of Aduhelm, the deputy director of the FDA’s office of neuroscience has called it quits after more than two decades at the agency.

Eric Bastings will now take over as VP of development strategy at Ionis Pharmaceuticals, the company said Wednesday, where he will provide senior clinical and regulatory leadership in support of Ionis’ pipeline.

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Sec­ondary patents prove to be key in biosim­i­lar block­ing strate­gies, re­searchers find

While the US biosimilars industry has generally been a disappointment since its inception, with FDA approving 33 biosimilars since 2015, just a fraction of those have immediately followed their approvals with launches. And more than a handful of biosimilars for two of the biggest blockbusters of all time — AbbVie’s Humira and Amgen’s Enbrel — remain approved by FDA but still have not launched because of legal settlements.

Hal Barron (GSK via YouTube)

GSK R&D chief Hal Bar­ron jumps ship to run a $3B biotech start­up, Tony Wood tapped to re­place him

In a stunning switch, GlaxoSmithKline put out word early Wednesday that R&D chief Hal Barron is exiting the company after 4 years — a relatively brief run for the man chosen by CEO Emma Walmsley in late 2017 to turn around the slow-footed pharma giant.

Barron is being replaced by Tony Wood, a close associate of Barron’s who’s taking one of the top jobs in Big Pharma R&D. He’ll be closer to home, though, for GSK. Barron has been running a UK and Philadelphia-based research organization from his perch in San Francisco.

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Chamath Palihapitiya and Pablo Legorreta

Bil­lion­aires Chamath Pal­i­hapi­tiya and Pablo Legor­re­ta hatch an $825M SPAC for cell ther­a­py biotech

Three years after Royalty Pharma chief Pablo Legorreta led a group of investors to buy up a pair of biotechs and create a new startup called ProKidney, the biotech is jumping straight into an $825 million public shell created by SPAC king and tech billionaire Chamath Palihapitiya.

ProKidney was founded 6 years ago but really got going at the beginning of 2019 with the $62 million acquisition of inRegen, which was working on an autologous — from the patient — cell therapy for kidney disease. After extracting kidney cells from patients, researchers expand the cells in the lab and then inject them back into patients, aiming to restore the kidneys of patients suffering from CKD.

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CBO: Medicare ne­go­ti­a­tions will ham­per drug de­vel­op­ment more than pre­vi­ous­ly thought

As President Biden’s Build Back Better Act — and, with it, potentially the Democrats’ last shot at major drug pricing reforms in the foreseeable future — remains on life support, the Congressional Budget Office isn’t helping their case.

The CBO last week released a new slide deck, outlining an update to its model on how Medicare negotiations might take a bite out of new drugs making it to market. The new model estimates a 10% long-term reduction in the number of new drugs, whereas a previous CBO report from August estimated that 8% fewer new drugs will enter the market over 30 years.

Joshua Brumm, Dyne Therapeutics CEO

FDA or­ders DMD tri­al halt, rais­ing ques­tions about a whole class of promis­ing drugs

Dyne Therapeutics’ stock took a nasty hit this morning after the biotech put out word that the FDA had slapped a clinical hold on their top program for Duchenne muscular dystrophy. And now speculation is bouncing around Biotwitter that there could be a class effect at work here that would implicate other drug developers in the freeze.

Dyne execs didn’t have a whole lot to say about why the FDA sidelined their IND for DYNE-251 in DMD while “requesting additional clinical and non-clinical information for” the drug.

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CEO Lex Rovner (64x Bio)

A George Church spin­out fight­ing the vi­ral vec­tor bot­tle­neck in cell and gene ther­a­py lands $55M

A synthetic biology company spun out of George Church’s lab is set to tackle the gene therapy manufacturing bottleneck, and it just landed $55 million in a Series A financing round to do so.

64x Bio comes out of the Harvard Department of Genetics. CEO Lex Rovner and her team — which right now, sits around 10 people — are looking to tackle a key hurdle for major companies: manufacturing cell and gene therapies.