FDA pan­el of­fers a wa­ver­ing thumbs up for Eli Lil­ly's 2 mg baric­i­tinib, thumbs down on 4 mg

A large pan­el of out­side rheuma­toid arthri­tis ex­perts gath­ered at the FDA to dis­cuss Eli Lil­ly’s $LLY con­tro­ver­sial re-ap­pli­ca­tion for an ap­proval of baric­i­tinib, vot­ing in lop­sided fa­vor of the ef­fi­ca­cy and safe­ty of the 2 mg dose of the rheuma­toid arthri­tis drug, but turned their thumbs down on the 4 mg dose.

Ten vot­ed in fa­vor of the risk/ben­e­fit bal­ance of the 2 mg dose, 5 against. The num­bers were re­versed for the 4 mg, falling 10 against and 5 in fa­vor.

Jose Sch­er

These ex­pert votes hinged on a con­sid­er­able amount of con­fu­sion and un­cer­tain­ty, though, which sev­er­al mem­bers were quick to ac­knowl­edge.

Said one mem­ber who vot­ed yes on the ad­e­qua­cy of the safe­ty da­ta of the 2 mg dose: “This whole thing is a house of cards and I could have gone ei­ther way.”

An­oth­er: ”My best guess is yes.”

Er­i­ca Brit­tain: “I vot­ed yes, I could have def­i­nite­ly vot­ed no.”

“We still don’t have enough da­ta,” said one mem­ber who vot­ed in fa­vor of the ad­e­qua­cy of the 2 mg dose.

“I would urge the spon­sor to get as much da­ta as pos­si­ble on the safe­ty side,” com­ment­ed com­mit­tee chair Jose Sch­er, who vot­ed against both the 2 mg and 4 mg dos­es based on in­ad­e­quate safe­ty da­ta.

That all could emerge as a ma­jor headache for Eli Lil­ly and its part­ners at In­cyte $IN­CY, as the com­pa­ny wants to start treat­ment-re­sis­tant pa­tients at 4 mg and then ta­per down to 2 mg if they sta­bi­lize their dis­ease.

Lil­ly’s shares ini­tial­ly dropped 3% in ear­ly trad­ing Tues­day, then man­aged to climb back up in­to the green, bare­ly. In­cyte shares, though, are still down 5% in mid-morn­ing trad­ing.

The pan­el dis­cus­sion in­clud­ed a me­an­der­ing se­ries of com­ments, with some voic­es sup­port­ing an ap­proval to of­fer a new op­tion for pa­tients and a few flag­ging some se­ri­ous safe­ty is­sues and oth­ers un­cer­tain just what was demon­strat­ed by the da­ta on dis­play.

On one point, the ad­vi­so­ry com­mit­tee found clear con­sen­sus around ef­fi­ca­cy. By a vote of 14 to 1 they con­clud­ed that there was clear ev­i­dence of the “sub­stan­tial ev­i­dence” that backed the drug’s ef­fi­ca­cy, with a unan­i­mous vote in fa­vor of ef­fi­ca­cy as a sec­ond-line ther­a­py af­ter pa­tients had failed on their front­line drug.

Much of the dis­cus­sion, though, cen­tered on the safe­ty of the drug, where reg­u­la­tors raised some of their most se­ri­ous ob­jec­tions to the drug, with a star­tling sig­nal on throm­boem­bolism.

One com­mit­tee mem­ber not­ed a dis­cus­sion con­cern­ing whether rheuma­tol­o­gists are used to look­ing for and mon­i­tor­ing for ad­verse events. But, he added, “rheuma­tol­o­gists do not typ­i­cal­ly look for throm­boem­bol­ic events, that’s not on the list of things that are tra­di­tion­al­ly watched for.”

There was a con­sid­er­able dis­cus­sion whether the com­mit­tee had the da­ta need­ed to make a con­clu­sion on the drug’s safe­ty, par­tic­u­lar­ly when it came to the 2 mg dose. 

“None of these stud­ies are pow­ered to look for rare events,” said Sch­er, high­light­ing stud­ies that weren’t pow­ered to de­ter­mine the risk of throm­boem­bolisms, or blood clots, and not­ing that there was con­sid­er­able con­fu­sion about the da­ta and the con­clu­sions that could be drawn from them — par­tic­u­lar­ly re­lat­ing to the 2 mg dose, where the da­ta were lack­ing.

Baric­i­tinib is a re­mark­able test case for the FDA. Re­ject­ed in 2017 in a stun­ning set­back for a drug that had been billed as a block­buster in the mak­ing, the agency re­versed course and al­lowed Lil­ly to re­file for an ap­proval as a sec­ond-line ther­a­py with­out the added da­ta that had been in­sist­ed on. The agency’s re­view makes clear that while Eli Lil­ly in­ves­ti­ga­tors pro­vid­ed more in­for­ma­tion, none of it ad­dressed their core con­cerns, es­pe­cial­ly re­gard­ing a high­er rate of throm­bo­sis that ap­peared for the first time in the field.

FDA re­view­ers dis­agreed on the da­ta of­fered for the 2 mg and 4 mg dos­es, with some will­ing to wave it through and oth­ers not­ing that the study da­ta for the 2 mg nev­er pro­vid­ed suf­fi­cient in­for­ma­tion for a de­ci­sion on safe­ty and ef­fi­ca­cy. There was al­so no con­sis­tent da­ta to back up the 4 mg dose over the 2 mg dose, ac­cord­ing to reg­u­la­tors. 

Even if it gets an ap­proval now, Lil­ly is go­ing to have an up­hill fight against Pfiz­er’s Xel­janz (to­fac­i­tinib), the first JAK in­hibitor to make it to the mar­ket — with­out the harsh FDA crit­i­cism or is­sues with throm­bo­sis that promise to cap­size Lil­ly’s launch.

Why of­fer an ap­proval now if there are oth­er drugs on the mar­ket that could do as well or bet­ter? And if it is ap­proved, will this drug be re­served for last-chance op­por­tu­ni­ties?

“We know we didn’t make your lives any eas­i­er,” said Sch­er as he turned at the end to the FDA’s rep­re­sen­ta­tives.

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Amarin had been fighting to keep key patents under lock and key — and away from generic rivals — for another 10 years, but District Court Judge Miranda Du in Las Vegas ruled against the biotech. She ruled that:
(A)ll the Asserted Claims are invalid as obvious under 35 U.S.C.§ 103. Thus, the Court finds in favor of Defendants on Plaintiff’s remaining infringementclaim, and in their favor on their counterclaims asserting the invalidity of the AssertedClaims under 35 U.S.C. § 103.

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