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

Albert Bourla (Evan Vucci, AP Images)

Af­ter a post-mar­ket­ing tri­al for Pfiz­er’s Xel­janz turned 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.

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A nurse administers a COVID-19 booster shot to Joe Rigdon at a vaccination site in Eastmonte Park, Altamonte Springs. (Photo by Paul Hennessy/SOPA Images/LightRocket via Getty Images)

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Jay Bradner, President, Novartis Institutes for BioMedical Research

John Carroll: Well, hello everybody. This is John Carroll. I’m the editor of Endpoints News, the editor and founder of Endpoints News. I’m here with Jay Bradner, the president of the Novartis Institutes for BioMedical Research. Jay, we’re going to be talking about ASH in just a second, but you’ve just recently celebrated your sixth anniversary as president of NIBR. And I’m curious, it’s such a significant amount of time for anybody to spend in one career phase. And looking back over the last six years, is everything fundamentally different about the research process and the translational arena that you’re in?

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Harpreet Singh, Immatics CEO (Credit: Allogeneic Cell Therapies Summit)

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Robert Califf (L) shakes hands with Sen. Mitt Romney (R-UT) at Califf’s confirmation hearing for FDA commissioner, Dec. 14, 2021 (Graeme Sloan/Sipa via AP Images)

Rob Califf, the famous cardiologist from Duke University, is likely to return to the top of the FDA, this time under the Biden administration.

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Soon after San Francisco-based Genentech won an EUA for tocilizumab as a treatment for hospitalized Covid patients last summer, the company announced a shortage of the drug while pointing to the emergence of the Delta variant and the slowing of vaccination rates across the US.

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During the Covid-19 pandemic, local pharmacies were not only key purveyors of prescriptions and hand sanitizer, but also important testing and vaccine delivery locations. Next up? Clinical trial sites. That’s according to a recent PwC Health report that lays out the case for both pharma and pharmacies — and why it’s more probable than ever.

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