Peter Marks (Greg Nash/Pool via AP)

Even FDA's Pe­ter Marks is wor­ried about the com­mer­cial vi­a­bil­i­ty of gene and cell ther­a­pies

When blue­bird bio’s gene ther­a­py to treat be­ta tha­lassemia won Eu­ro­pean ap­proval in 2019, the near­ly $2 mil­lion per pa­tient price tag for the po­ten­tial cure seemed like a sur­mount­able hur­dle.

Fast for­ward two years lat­er, and blue­bird has with­drawn Zyn­te­glo, the be­ta thal drug, along with the rest of its gene ther­a­py port­fo­lio from Eu­rope, which the com­pa­ny said is gen­er­al­ly un­will­ing to pay a fair price for the treat­ment.

In Ger­many, the on­ly coun­try for which blue­bird dis­closed de­tails, au­thor­i­ties of­fered $790,000 for the one-time treat­ment, with the pay­out mov­ing to $950,000 if the ther­a­py is still work­ing af­ter five years. That’s rough­ly in line with the $900,000 price tag Wall Street an­a­lysts ex­pect­ed blue­bird to put on the ther­a­py pri­or to launch. But blue­bird want­ed $1.8 mil­lion paid over 5 years, with pay­outs con­di­tioned on a pa­tient’s re­sponse.

This and oth­er ex­am­ples (see Gly­bera) have raised ques­tions about the vi­a­bil­i­ty of the gene and cell ther­a­py space, par­tic­u­lar­ly as it’s able to tar­get small­er and small­er groups of pa­tients.

Pe­ter Marks, di­rec­tor of the cen­ter at FDA that reg­u­lates these ther­a­pies, ad­dressed this is­sue of fi­nan­cial vi­a­bil­i­ty head on at a con­fer­ence on Tues­day morn­ing, par­tic­u­lar­ly as it re­lates to in­di­ca­tions where there may on­ly be sev­er­al dozen pa­tients world­wide.

The prob­lem is spon­sors are see­ing this group of on­ly 20 to 40 pa­tients per year for one ther­a­py as com­mer­cial­ly non­vi­able, Marks ex­plained. If there was bet­ter man­u­fac­tur­ing of small­er batch­es of AAV vec­tors for gene ther­a­pies, for ex­am­ple, he said, there might be a way to put to­geth­er a port­fo­lio of these small­er-pop­u­la­tion prod­ucts that would then be vi­able.

While it’s un­ortho­dox for any se­nior FDA of­fi­cial to ad­dress the com­mer­cial vi­a­bil­i­ty of any med­ical prod­ucts, and the FDA re­cent­ly ad­dressed some of the safe­ty ques­tion marks around gene and cell ther­a­pies, Marks specif­i­cal­ly ad­dressed these small­er groups of gene ther­a­pies, not­ing, “We’re all a lit­tle gun-shy when we see pro­grams be­ing dropped, and that means we have to find a way for­ward to re­store con­fi­dence for these small­er pop­u­la­tions.”

Part of the path for­ward in­cludes fig­ur­ing out how to price these ex­pen­sive and ex­pen­sive-to-make ther­a­pies, he said.

“Re­im­burse­ment is the 800 pound go­ril­la in the room,” Marks told the crowd vir­tu­al­ly on Tues­day at the AS­GCT’s 25th an­nu­al meet­ing in Wash­ing­ton, DC, not­ing that some of the ac­cel­er­at­ed ap­provals “make peo­ple shud­der be­cause of con­cerns” about pric­ing and risk-shar­ing mod­els.

“Once there are 5 to 8 gene ther­a­pies, things will work them­selves out,” Marks added, of­fer­ing the ex­am­ple of No­var­tis’ spinal mus­cu­lar at­ro­phy gene ther­a­py Zol­gens­ma as a case where:

the val­ue propo­si­tion is so over­whelm­ing, it’s hard to think of not to cov­er that. But for oth­ers, where it’s not a life or death is­sue, it will be more chal­leng­ing and will be sim­i­lar to what our Eu­ro­pean col­leagues see. How that gets re­solved will com­plete­ly af­fect how many peo­ple go in­to this field to de­vel­op ther­a­pies.

He al­so sug­gest­ed a much more in­ter­na­tion­al­ly har­mo­nized ap­proach for reg­u­lat­ing these gene ther­a­pies for small­er, rare dis­ease pa­tient groups, which might have dozens of pa­tients glob­al­ly.

Marks sug­gest­ed a way to move to a more com­mon ap­pli­ca­tion process glob­al­ly, not­ing, “Maybe we won’t get some of the pre­clin­i­cal in­fo we do care about, but can live with­out, and in turn, pa­tients get ac­cess in home coun­tries with­out hav­ing to trav­el” to gain ac­cess to these ther­a­pies. “We have to give se­ri­ous con­sid­er­a­tion to these prod­ucts. If it’s de­signed to 10-20 per 100 mil­lion peo­ple, any one coun­try won’t have enough pa­tients to sus­tain com­mer­cial­iza­tion,” he said.

Marks pre­vi­ous­ly penned an NE­JM ed­i­to­r­i­al on these in­di­vid­u­al­ized treat­ments and how to reg­u­late them in 2019.

On ques­tions re­lat­ed to ac­cel­er­at­ed ap­proval re­forms, which have been in the news as Con­gress at­tempts to tack sev­er­al of these re­forms on­to must-pass FDA user fee leg­is­la­tion, Marks said there’s a need for the AA path­way in the cell and gene ther­a­py space. Some neu­rode­gen­er­a­tive dis­eases, for in­stance, he said, “If we take away the abil­i­ty to use sur­ro­gate end­points, we would have a lot of trou­ble see­ing these prod­ucts de­vel­oped.”

But he did ac­knowl­edge that the ac­cel­er­at­ed ap­proval path­way “has been used like an off-ramp” lead­ing to prob­lems in the past.

“Sur­pris­es are not need­ed here in the gene ther­a­py field. The idea here is agree­ing up­front on the sur­ro­gate, there’s less a chance for sur­pris­es. What we will be do­ing is mov­ing these dis­cus­sions up­front,” Marks said.

In re­sponse to a ques­tion from the au­di­ence on what the timetable might look like for get­ting back to tele­con­fer­enc­ing be­tween CBER and spon­sors, Marks ac­knowl­edged the staff short­ages and that this “is not an op­ti­mal sit­u­a­tion. Even pri­or to the pan­dem­ic, we were un­der­staffed. My key for 2022 is a re­cov­ery theme — my hope is that as we ease in­to the next cal­en­dar year, more ro­bust ex­changes with the agency oc­cur, in­clud­ing tele­con­fer­ences.”

Up­dat­ed: FDA re­mains silent on or­phan drug ex­clu­siv­i­ty af­ter last year's court loss

Since losing a controversial court case over orphan drug exclusivity last year, the FDA’s Office of Orphan Products Development has remained entirely silent on orphan exclusivity for any product approved since last November, leaving many sponsors in limbo on what to expect.

That silence means that for more than 70 orphan-designated indications for more than 60 products, OOPD has issued no public determination on the seven-year orphan exclusivity in the Orange Book, and no new listings of orphan exclusivity appear in OOPD’s searchable database, as highlighted recently by George O’Brien, a partner in Mayer Brown’s Washington, DC office.

Big week for Alzheimer’s da­ta; As­traZeneca buys cell ther­a­py start­up; Dig­i­tal ther­a­peu­tics hits a pay­er wall; and more

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Illustration: Assistant Editor Kathy Wong for Endpoints News

As mon­ey pours in­to dig­i­tal ther­a­peu­tics, in­sur­ance cov­er­age crawls



Talk therapy didn’t help Lily with attention deficit hyperactivity disorder, or ADHD. But a video game did.

As the 10-year-old zooms through icy waters and targets flying creatures on the snow-capped planet Frigidus, she builds attention skills, thanks to Akili Interactive Labs’ video game EndeavorRx. She’s now less anxious and scattered, allowing her to stay on a low dose of ADHD medication, according to her mom Violet Vu.

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John Evans, Beam Therapeutics CEO

Beam's base-edit­ed al­lo­gene­ic CAR-T gets FDA go-ahead af­ter four-month wait

The FDA wanted more information on four key areas before it would let Beam Therapeutics proceed with human testing for a cell therapy in a certain type of leukemia. It appears the biotech has answered the agency’s queries.

The US regulator cleared the base-edited, off-the-shelf CAR-T, Beam said Friday morning, lifting a hold from this summer. More details on specific next steps for the Phase I will come out next year, the Boston-area biotech said.

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Am­gen, years be­hind ri­vals, says PhI obe­si­ty drug shows dura­bil­i­ty signs

While NBC ran “The Biggest Loser” for 17 seasons, deemed toxic by critics for the reality show’s punishing exercise and diet upheavals, researchers in pharmaceutical labs have been attempting to create prescription drugs that induce weight loss — and one pharma betting it can require less frequent dosing is out with a new crop of data.

Amgen was relatively late to the game compared to its approved competitor Novo Nordisk and green light-approaching rival Eli Lilly. But early data suggested Amgen’s AMG 133 led to a 14.5% weight reduction in the first few months of dosing, buoying shares earlier this fall, and now the California pharma is out with its first batch of durability data showing that figure fell slightly to 11.2% about 150 days after the last dose. Amgen presented at the 20th World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease on Saturday afternoon.

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Eli Lil­ly’s Alzheimer’s drug clears more amy­loid ear­ly than Aduhelm in first-ever head-to-head. Will it mat­ter?

Ahead of the FDA’s decision on Eli Lilly’s Alzheimer’s drug donanemab in February, the Big Pharma is dropping a first cut of data from one of the more interesting trials — but less important in a regulatory sense — at an Alzheimer’s conference in San Francisco.

In the unblinded 148-person study, Eli Lilly pitted its drug against Aduhelm, Biogen’s drug that won FDA approval but lost Medicare coverage outside of clinical trials. Notably, the study didn’t look at clinical outcomes, but rather the clearance of amyloid, a protein whose buildup is associated with Alzheimer’s disease, in the brain.

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Tim Van Hauwermeiren, argenx CEO

Ar­genx pur­chas­es $100M+ FDA pri­or­i­ty re­view vouch­er from blue­bird bio

Argenx’s Vyvgart is due for a speedy review at the FDA, thanks to a $102 million priority review voucher (PRV).

The Netherland-based biotech picked up the PRV from bluebird bio, the companies announced on Wednesday. PRVs shorten a drug’s FDA review period from 10 months to 6 months, though they often sell on the open market for around $100 million each.

Argenx plans on using the express ticket on efgartigimod, its neonatal Fc receptor (FcRn) blocker marketed as Vyvgart for adults with generalized myasthenia gravis (gMG). While Vyvgart won its first approval last December for the chronic neuromuscular disease — which is characterized by difficulties with facial expression, speech, swallowing and breathing — CEO Tim Van Hauwermeiren said in a news release that he plans to “be active in fifteen disease targets by 2025.”

Lex­i­con slams FDA over hear­ing de­nial fol­low­ing a CRL for its SGLT2 in­hibitor can­di­date

Lexicon Pharmaceutical is not giving up on its Type I diabetes candidate, despite FDA’s repeated rejections. This week the company laid out is argument again for a hearing on sotagliflozin in response to the FDA’s most recent denial.

The issue goes back to March 2019 when the FDA made very clear to Lexicon and its now departed partner Sanofi that it would not approve their application for a potential Type I diabetes drug because it does not appear to be safe.

US month­ly costs for biosim­i­lars 'sub­stan­tial­ly high­er' than Ger­many or Switzer­land, JA­MA re­search finds

As the global biologics market is expected to hit nearly the half-trillion-dollar mark this year, new JAMA research points to the importance of timely biosimilar entry, particularly as fewer biosimilars are entering the US than in Europe, and as monthly treatment costs for biosimilars were “substantially higher” in the US compared with Germany and Switzerland.

Among the three countries, biosimilar market share at launch was highest in Germany, but increased at the fastest rate in the US, the authors from the University of Zurich’s Institute of Law wrote in JAMA Network Open today.