FDA cites litany of er­rors at Lon­za Hous­ton plant at the cen­ter of Bris­tol My­ers CVR de­ba­cle

In­vestors’ some­what long­shot bet on a $9 CVR tied to Bris­tol My­ers Squibb’s ac­qui­si­tion of Cel­gene came to a screech­ing halt last month af­ter the FDA took too long to de­cide on CAR-T can­di­date liso-cel. One of the po­ten­tial cul­prits in that de­lay, a De­cem­ber in­spec­tion of a con­tract man­u­fac­tur­er, now ap­pears to have played a big role af­ter the FDA cit­ed a num­ber of is­sues at that plant.

In a Form 483  pub­lished on­line this week, the FDA blast­ed Lon­za Hous­ton, one of the con­tract man­u­fac­tur­ers for liso-cel, for a litany of er­rors, in­clud­ing mis­la­bel­ing, prod­ucts for the US and EU drug mar­kets stored in the same bins, “poor­ly main­tained” freez­er units, and ex­pired batch­es of in­gre­di­ents that weren’t prop­er­ly dis­posed of.

Those is­sues were found dur­ing an ear­ly De­cem­ber in­spec­tion and out­lined in the four-ob­ser­va­tion Form 483. De­spite Bris­tol re­spond­ing to con­cerns at the site with­in eight days, it wasn’t enough to get liso-cel on track for an ap­proval by year-end — one of the key check­points for the $9 CVR.

De­spite those is­sues, Lon­za ul­ti­mate­ly be­lieves a de­lay in the planned in­spec­tion at its site due to Covid-19 may have ul­ti­mate­ly tor­pe­doed the ap­proval. In a state­ment Wednes­day, Lon­za spokesper­son San­na Fowler said the com­pa­ny is “rapid­ly ad­dress­ing” the FDA’s ob­ser­va­tions from the De­cem­ber site in­spec­tion, and isn’t aware of any rea­sons that would fur­ther de­lay the ap­proval of the drug in ques­tion—Bris­tol My­ers Squibb’s liso-cel CAR-T ther­a­py.

“Lon­za reg­u­lar­ly re­ceives vis­its from in­ter­na­tion­al reg­u­la­to­ry bod­ies, in­clud­ing the FDA and in a typ­i­cal year we host around ten FDA in­spec­tions,” Fowler wrote in an email. “We take com­pli­ance very se­ri­ous­ly and do every­thing we can to en­sure that all cus­tomers and stake­hold­ers, in­clud­ing reg­u­la­tors, are sat­is­fied. When is­sues come to our at­ten­tion, we ad­dress them ex­pe­di­tious­ly and ef­fec­tive­ly, as is the case here.”

Lon­za, Fowler said, re­mains com­mit­ted to sup­port­ing Bris­tol My­ers Squibb “in their goal of bring­ing liso-cel to pa­tients with re­lapsed or re­frac­to­ry large B-cell lym­phoma.”

A week­long in­spec­tion of the Lon­za site was part of the liso-cel drug ap­pli­ca­tion re­view. Due to Covid-19 re­stric­tions, though, an in­spec­tion ini­tial­ly sched­uled for April was sig­nif­i­cant­ly de­layed to Dec. 3-10.

This de­lay, ob­ser­va­tions aside, had dras­tic and ex­pen­sive ram­i­fi­ca­tions for Bris­tol in­vestors, who were re­ly­ing on a PDU­FA ap­proval for liso-cel by Dec. 31, 2020 to cash in on a $6.4 bil­lion pay­day linked to the com­pa­ny’s Cel­gene merg­er. While the Form 483 it­self isn’t a death nail to an even­tu­al liso-cel ap­proval, it fur­ther de­layed those reg­u­la­to­ry process­es and firm­ly shut the door on any hopes those in­vestors had of the ad­di­tion­al pay­day.

When the FDA fi­nal­ly did come to in­spect Lon­za’s site, it clear­ly wasn’t quite pre­pared.

The Form 483 notes that among the afore­men­tioned ob­served is­sues, fa­cil­i­ty work­ers ap­par­ent­ly failed to ver­i­fy the iden­ti­ty of each new batch of raw ma­te­ri­als be­fore they were re­leased to the man­u­fac­tur­ing process­es. Writ­ten pro­ce­dures weren’t al­ways fol­lowed, and the in­spec­tors said they ob­served one case of asep­tic op­er­a­tion con­trol that was in­ad­e­quate.

On Jan. 1, Bris­tol My­ers Squibb is­sued a brief and some­what cryp­tic press re­lease up­dat­ing the sta­tus of the liso-cel ap­pli­ca­tion, and said that both Lon­za and the com­pa­ny “re­spond­ed ex­pe­di­tious­ly” to ob­ser­va­tions from the Dec. 3-10 in­spec­tion, but didn’t men­tion the Form 483.

Bris­tol My­ers Squibb hasn’t pub­licly com­ment­ed on the liso-cel ap­pli­ca­tion process since. In a state­ment, a com­pa­ny spokesper­son said the work to get the drug ap­proved con­tin­ues but didn’t specif­i­cal­ly ad­dress its part­ner­ship with Lon­za, the Form 483 ob­ser­va­tions or the CVR loss­es im­posed by the de­lay.

“The com­pa­ny con­tin­ues to work close­ly with the FDA to sup­port the on-go­ing re­view of the BLA for liso-cel, the tim­ing of which is set by the FDA,” the spokesper­son said. “We are com­mit­ted to bring­ing liso-cel to pa­tients with re­lapsed or re­frac­to­ry large B-cell lym­phoma who still have sig­nif­i­cant un­met needs.”

Biotech in­vestors and CEOs see two paths to growth, but are they equal­ly vi­able?

The dynamic in the biotech market has been highly volatile in the last few years, from the high peaks immediately after the COVID vaccine in 2021, to the lowest downturns of the last 20 years in 2022. This uncertainty makes calling the exact timing of the market’s turn something of a fool’s errand, according to Dr. Chen Yu, Founder and Managing Partner of TCG Crossover (TCG X). He speaks with RBC’s Noël Brown, Head of US Biotechnology Investment Banking, about the market’s road ahead and two possible paths for growth.

Dave Marek, Myovant CEO

My­ovant board balks as ma­jor­i­ty own­er Sum­it­o­mo swoops in with a $2.5B deal to buy them out

Three years after Sumitomo scooped up Roivant’s 46% stake in the publicly traded Myovant $MYOV as part of a 5-company, $3 billion deal, they’re coming back for the whole thing.

But these other investors at Myovant want more than what the Japanese pharma company is currently offering to pay at this stage.

Sumitomo is bidding $22.75 a share for the outstanding stock, which now represents 48% of the company after Sumitomo bumped its ownership since the original deal with Roivant. Myovant, however, created a special committee on the board, and they’re shaking their heads over the offer.

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Casey McPherson shows his daughters Rose (left) and Weston around Everlum Bio, a lab that he co-founded to spark a treatment for Rose and others with ultra-rare conditions. (Ilana Panich-Linsman)

Fa­ther starts lab af­ter in­tel­lec­tu­al prop­er­ty is­sues stymie rare dis­ease drug de­vel­op­ment

Under bright lab lights, Casey McPherson holds his 6-year-old daughter, Rose. His free hand directs Rose’s gaze toward a computer screen with potential clues in treating her one-of-a kind genetic condition.

Gray specks on the screen show her cells that scientists reprogrammed with the goal of zeroing in on a custom medicine. McPherson co-founded the lab, Everlum Bio, to spark a treatment for Rose — and others like her. A regarded singer-songwriter, McPherson never imagined going into drug development.

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Take­da to pull key hy­poparathy­roidism drug from the mar­ket af­ter years of man­u­fac­tur­ing woes

Takeda on Tuesday morning made an announcement that almost 3,000 people with the rare disease known as hypoparathyroidism were fearing.

Due to unresolved supply issues and manufacturing woes, Takeda said it will cut its losses and discontinue its hypoparathyroidism drug, known as Natpara (parathyroid hormone), halting all manufacturing of the drug by the end of 2024, but the entire inventory will be available until depleted or expired, a company spokesperson said via email.

Vlad Coric, Biohaven CEO

Vlad Coric charts course for new Bio­haven with neu­ro­science push and Big Phar­ma vets on board

What’s Biohaven without its CGRP portfolio? That’s what CEO Vlad Coric is tasked with deciding as he maps out the new Biohaven post-Pfizer takeover.

Pfizer officially scooped up Biohaven’s CGRP assets on Monday, including blockbuster migraine drug Nurtec and the investigational zavegepant, for $11.6 billion. As a result, Coric spun the broader pipeline into an independent company on Tuesday — with the same R&D team behind Nurtec but about 1,000 fewer staffers and a renewed focus on neuroscience and rare disease.

In AstraZeneca's latest campaign, wild eosinophils called Phils personify the acting up often seen in uncontrolled asthma

As­traZeneca de­buts an­noy­ing pur­ple ‘Phil’ crea­tures, per­son­i­fied asth­ma eosinophils ‘be­hav­ing bad­ly’

There are some odd-looking purple creatures lurking around the halls of AstraZenca lately. The “Phil” character cutouts are purple, personified eosinophils with big buggy eyes and wide mouths, and they’re a part of AZ’s newest awareness effort to help people understand eosinophilic asthma.

The “Asthma Behaving Badly” characters aren’t only on the walls at AZ to show the new campaign to employees, however. The “Phils” are also showing up online on the campaign website, and in digital and social ads and posts on Facebook and Instagram.

Ying Huang, Legend CEO

Lentivi­ral vec­tor ramp-up: J&J and Leg­end to in­vest $500M in New Jer­sey man­u­fac­tur­ing to sup­port Carvyk­ti

In response to a question on manufacturing scale at Legend Biotech’s R&D day yesterday, the company’s top exec said its partnership with Johnson & Johnson will be doubling its investment in its New Jersey manufacturing center and will be investing a total of $500 million.

With an eye on their BCMA-directed CAR-T therapy Carvykti (cilta-cel), approved in February as a fifth-line treatment for multiple myeloma, Legend CEO Ying Huang said that the ramp-up in production and the decision to manufacture its own lentiviral vectors — currently in shortage worldwide — means they won’t have to deal with that shortage.

Kite Phar­ma gets FDA to sign off on new Cal­i­for­nia-based vec­tor man­u­fac­tur­ing fa­cil­i­ty

Kite Pharma just got FDA approval to kick off operations at a new manufacturing campus.

The cancer-focused, CAR-T cell therapy player made the announcement Monday, saying that the federal regulatory agency gave the green light to Kite’s 100,000 square-foot, retroviral vector manufacturing facility in Oceanside, CA.

Kite’s global head of technical operations Chris McDonald tells Endpoints News that the facility has been in the works for about four years, after Kite teamed up with its parent company Gilead. Gilead acquired Kite Pharma for just shy of $12 billion in 2017.

Big Phar­ma heavy­weights seek tweaks to FDA's clin­i­cal out­come as­sess­ment guid­ance

Pfizer, GSK, Janssen, Regeneron, Boehringer Ingelheim and at least a half dozen other companies are calling on the FDA to provide significantly more clarity in its draft guidance from this summer on clinical outcome assessments, which are a type of patient experience.

The draft is the third in a series of four patient-focused drug development guidance documents that the FDA had to create as part of the 21st Century Cures Act, and they describe how stakeholders (patients, caregivers, researchers, medical product developers and others) can collect and submit patient experience data and other relevant information for medical product development and regulatory decision-making.

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