Albert Bourla (Evan Vucci, AP Images)

Amid safe­ty con­cerns, FDA grants two new JAK ap­provals — but with added warn­ings and a key la­bel change

Af­ter a post-mar­ket­ing tri­al for Pfiz­er’s Xel­janz turned up con­cern­ing safe­ty re­sults at the be­gin­ning of the year, thwart­ing the whole JAK class, the FDA is fi­nal­ly rolling out some new ap­provals — but with added warn­ings and a key la­bel change.

Both Xel­janz and Ab­b­Vie’s Rin­voq got cleared for new in­di­ca­tions on Tues­day, but on one con­di­tion: They can on­ly be tak­en af­ter a pa­tient has failed on one or more tu­mor necro­sis fac­tor (TNF) block­ers, like Hu­mi­ra or En­brel.

Ear­li­er this month, the FDA slapped boxed warn­ings on the la­bels of Xel­janz, Rin­voq and Eli Lil­ly’s Olu­mi­ant, flag­ging the risk of car­dio­vas­cu­lar events such as heart at­tack or stroke in high-risk pa­tients who are 50 years and old­er, es­pe­cial­ly those with oth­er risk fac­tors such as cur­rent or past smok­ers.

Xel­janz is now ap­proved for adults with ac­tive anky­los­ing spondyli­tis, a rare type of arthri­tis that caus­es pain and stiff­ness in the spine. And Rin­voq pulled a win in adults with ac­tive pso­ri­at­ic arthri­tis, a type of in­flam­ma­to­ry arthri­tis that caus­es joint pain, stiff­ness and swelling.

The lat­est fall­out over JAK safe­ty be­gan back in Jan­u­ary, when Xel­janz failed a six-year post-mar­ket­ing safe­ty study across 4,362 rheuma­toid arthri­tis pa­tients. Re­searchers found that those who re­ceived ei­ther a low or high dose of Xel­janz ex­pe­ri­enced more ma­jor car­dio­vas­cu­lar events — such as stroke and heart at­tack — than those on Hu­mi­ra or En­brel. They al­so had high­er rates of can­cer, with Pfiz­er fail­ing to hit non-in­fe­ri­or­i­ty on both pri­ma­ry end­points.

The study re­newed some dif­fi­cult ques­tions for JAK in­hibitors more broad­ly, a class that gen­er­at­ed sig­nif­i­cant ef­fi­ca­cy in au­toim­mune con­di­tions but faced re­peat­ed safe­ty con­cerns.

In the first week of De­cem­ber, the FDA con­clud­ed that there’s an in­creased risk of se­ri­ous heart-re­lat­ed events such as heart at­tack or stroke, can­cer, blood clots and death as­so­ci­at­ed with Xel­janz, and put up­dat­ed warn­ings on that drug and two oth­ers. Al­though Olu­mi­ant and Rin­voq hadn’t been stud­ied in large safe­ty tri­als, reg­u­la­tors de­cid­ed that they may pose sim­i­lar risks, as they share the same mech­a­nism of ac­tion.

In­vestors were mut­ed on the news of Ab­b­Vie and Pfiz­er’s new ap­provals, with the com­pa­ny’s stock, $AB­BV and $PFE, up about 1% in pre-mar­ket trad­ing on Tues­day.

The Xel­janz ap­proval is based on da­ta from a Phase III tri­al, show­ing that twice-dai­ly 5 mg dos­es of the block­buster drug helped 56.4% of pa­tients achieve an im­prove­ment of at least 20% on the As­sess­ment in Spondy­loArthri­tis in­ter­na­tion­al So­ci­ety scale (ASAS20), com­pared to just 29.4% of place­bo pa­tients (p<0.0001).

Just over 40% of pa­tients on Xel­janz achieved an ASAS40 re­sponse, com­pared to 12.5% on place­bo, ac­cord­ing to Pfiz­er. The safe­ty pro­file was sim­i­lar to that in ap­proved in­di­ca­tions of rheuma­toid arthri­tis and pso­ri­at­ic arthri­tis, the com­pa­ny said.

Mean­while, Rin­voq helped pso­ri­at­ic arthri­tis pa­tients treat­ed with 15 mg dos­es achieve high­er ACR50 re­spons­es (an im­prove­ment of at least 50% on the Amer­i­can Col­lege of Rheuma­tol­ogy scale) com­pared to place­bo in two Phase III tri­als. In the tri­als, 38% and 32% of pa­tients on Rin­voq achieved ACR50, com­pared to 13% and 5% on place­bo, re­spec­tive­ly.

The Rin­voq arms al­so boast­ed 16% and 9% ACR70 re­spons­es, com­pared to 2% and 1% in the place­bo arms, re­spec­tive­ly. And the drug was seen to sig­nif­i­cant­ly in­hib­it the pro­gres­sion of struc­tur­al joint dam­age com­pared to place­bo, ac­cord­ing to Ab­b­Vie. The com­pa­ny said Rin­voq’s safe­ty pro­file was con­sis­tent with that in pa­tients with rheuma­toid arthri­tis.

Now, we’ll wait to see if the added warn­ings af­fect the drugs’ per­for­mances. Xel­janz pulled in $2.4 bil­lion in 2020, and Rin­voq was a bit be­hind it with $731 mil­lion in net sales.

The Fac­tors Dri­ving a Rapid Evo­lu­tion of Gene & Cell Ther­a­py and CAR-T Clin­i­cal Re­search in APAC

APAC is the fastest growing region globally for cell & gene therapy trials representing more than a third of all cell & gene studies globally, with China leading in the region. 

APAC is the leading location globally for CAR-T trials with China attracting ~60% of all CAR-T trials globally between 2015-2022. The number of CAR-T trials initiated by Western companies has rapidly increased in recent years (current CAGR of about 60%), with multiple targets being explored including CD19, CD20, CD22, BCMA, CD30, CD123, CD33, CD38, and CD138.

The End­points 11; blue­bird's $3M gene ther­a­py; Bio­gen tout new neu­ro da­ta; Harsh re­views for can­cer 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.

Reading about John Carroll’s pick of biotech’s most promising startups has become a treasured tradition. If you ever get curious about previous classes of the Endpoints 11, you can find all of them (plus a number of our other regular specials) here.

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EMA warns of short­ages of two Boehringer heart drugs due to a spike in de­mand

The EMA is putting EU member states on alert over the shortage of two drugs that counter heart attacks due to an uptick in demand.

On Friday, the EMA sent out a warning that two Boehringer Ingelheim drugs are experiencing a shortage: Actilyse and Metalyse. The drugs are used as emergency treatments for adults experiencing acute myocardial infarction, or a heart attack, by dissolving blood clots that have formed in the blood vessels.

The End­points 11: The top pri­vate biotechs in pur­suit of new drugs. Push­ing the en­ve­lope with pow­er­ful new tech­nolo­gies

Right around the beginning of the year, we got a close-up look at what happens after a boom ripples through biotech. The crash of life sciences stocks in Q1 was heard around the world.

In the months since, we’ve seen the natural Darwinian down cycle take effect. Reverse mergers made a comeback, with more burned out shells to go public at a time IPOs and road shows are out of favor. And no doubt some of the more recent arrivals on the investing side of the business are finding greener pastures.

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An­oth­er Cipla site lands a Form 483 over clean­ing is­sues and QC con­trols

A Cipla drug manufacturing site in India has once again landed in the crosshairs of FDA inspectors.

The facility in question is Cipla’s drug manufacturing facility in the village of Verna, in the state of Goa in India’s southwest. In a sign that foreign inspections might ramp up again, the FDA’s visit from Aug. 16 to Aug. 22 uncovered six observations.

The 11-page report noted that environmental monitoring at the site did not properly ensure that microbial contaminants were not making any impact in the aseptic filling areas. It also found that procedures meant to stop microbial contamination were not adequately conducted in aseptic areas of the facility.

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FDA ad­comm takes down Se­cu­ra Bio's leukemia drug af­ter fi­nal tri­al re­sults show po­ten­tial OS detri­ment

The FDA’s Oncologic Drugs Advisory Committee on Friday voted 8-4 against the benefit-risk profile of Secura Bio’s PI3K inhibitor Copiktra (duvelisib), which won approval in September 2018 as a third-line treatment for relapsed or refractory CLL or SLL, but updated pivotal trial results raised safety questions.

In addition to the serious and fatal toxicities of duvelisib, FDA speakers at the ODAC meeting pointed to an evolved treatment landscape for CLL and SLL, with targeted BTK or BCL2 inhibitors (front-line or second-line), and data pointing to a “potential detriment” in overall survival for duvelisib. But some ODAC members noted that the detriment was likely small and that there is some efficacy even as the data are difficult to interpret.

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Solicitor General Elizabeth Prelogar

Should SCO­TUS hear Am­gen's Repatha case? So­lic­i­tor gen­er­al says no

Back in April, Amgen said it was encouraged by the solicitor general’s anticipated review of its Supreme Court petition to rehear a Repatha patent case. They’re likely much less optimistic about the outcome now.

Solicitor General Elizabeth Prelogar wrote in a recent 27-page brief that Amgen’s arguments “lack merit and further review is not warranted.”

The case traces back to a suit filed in 2014 against Sanofi and Regeneron’s Praluent, which ended up beating Amgen’s PCSK9 blockbuster Repatha to market by a month just a year later.

FDA's out­side ex­perts vote in fa­vor of Fer­ring's fe­cal trans­plant for C. dif­fi­cile, set­ting the stage for Seres

FDA’s outside advisors voted in favor of Ferring Pharmaceuticals’ RBX2660, an experimental poop-based drug implant that the company says would be the first microbiota-based live biotherapeutic to receive an FDA green light.

That was a point repeatedly discussed during the Vaccines and Related Biological Products Advisory Committee, or VRBPAC, meeting Thursday when evaluating Ferring’s fecal microbiota transplant, or FMT, for reducing the recurrence of Clostridioides difficile infection in adults who have received antibiotics. Multiple members brought up the need for a regulated product amid a landscape of unregulated FMTs already happening in clinical care.

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Richard Pazdur, FDA's OCE director (Flatiron Health via YouTube)

FDA's OCE makes the case for ac­cel­er­at­ed ap­proval rid­er in user fee reau­tho­riza­tion

Four experts from the FDA’s Oncology Center of Excellence took to the New England Journal of Medicine yesterday to make the case for not only improving the agency’s ability to expeditiously pull dangling accelerated approvals when, on the rare occasion, confirmatory trials fail, but also better building “quality and efficiency into the AA on-ramp.”

The timely perspective arrives as Congress has exactly one week left to draft, release and sign off on the reauthorized user fee deals before layoff notices will be sent to drug reviewers. That package, which is likely to hitch a ride with the continuing resolution, may or may not include several policy riders (opposed by Republicans), including one that would allow the FDA to require confirmatory trials to be underway before an AA is granted, and would improve the process by which FDA can withdraw AAs.