Safe­ty con­cerns lead to a split FDA pan­el vote on Sanofi/Lex­i­con di­a­betes drug

The first po­ten­tial pill for pa­tients with the less com­mon type 1 di­a­betes, who pro­duce no in­sulin, was the sub­ject of an atyp­i­cal hung ju­ry vote at an FDA pan­el on Thurs­day, in which ex­perts were di­vid­ed even­ly over whether the life-threat­en­ing risk of di­a­bet­ic ke­toaci­do­sis as­so­ci­at­ed with the drug off­set its ben­e­fit.

The drug, so­tagliflozin, from Lex­i­con Phar­ma and Sanofi is be­ing de­vel­oped for both type I and type II di­a­betes. It is de­signed to in­hib­it two pro­teins in­volved in glu­cose reg­u­la­tion: SGLT1, which is re­spon­si­ble for glu­cose re­ab­sorp­tion in the GI tract and SGLT2, which is re­spon­si­ble for glu­cose re­ab­sorp­tion by the kid­ney.  Many ex­ist­ing di­a­betes drugs on­ly tar­get SGLT2. Al­though the mol­e­cule is cur­rent­ly be­ing test­ed in a pletho­ra of tri­als in pa­tients with type II di­a­betes, the oral drug is cur­rent­ly un­der FDA re­view for type 1 di­a­bet­ics, who face mul­ti­ple dai­ly in­jec­tions of in­sulin, or use an in­sulin pump, to achieve glycemic con­trol.

The ap­pli­ca­tion for type 1 di­a­bet­ics was on the ba­sis of three late-stage tri­als. How­ev­er, an in­crease in the risk of di­a­bet­ic ke­toaci­do­sis (DKA) was ob­served with so­tagliflozin treat­ment — and it was this is­sue that was cen­tral to the split 8-8 vote on Thurs­day. Al­though the FDA is not ob­lig­at­ed to fol­low the rec­om­men­da­tions of the pan­el, it usu­al­ly does. In this case, the reg­u­la­tor has re­ceived a de­cid­ed­ly mixed mes­sage, and is set to make its de­ci­sion by March 22. The drug is al­so un­der EMA re­view.

In a re­port pub­lished on Tues­day, FDA re­view­ers ac­knowl­edged that the risk of DKA has been ob­served with SGLT2 in­hibitor use in type II di­a­bet­ics, and ex­ist­ing ap­proved drugs in the class car­ry warn­ings to high­light the risk. “While all pa­tients with type 1 di­a­betes may to some de­gree be at risk for DKA, so­tagliflozin ther­a­py clear­ly in­creas­es that risk, and the risk may be un­pre­dictable,” reg­u­la­to­ry staff wrote.

In the meet­ing of in­de­pen­dent ex­perts on Thurs­day, near­ly all pan­elists, re­gard­less of their fi­nal vote, agreed the drug — to be sold as Zyn­quista — would on­ly be ap­pro­pri­ate for a small sub­set of par­tic­u­lar­ly at­ten­tive type I di­a­betes pa­tients, in con­text of the DKA risk.

Stifel’s Stephen Wil­ley said he was sur­prised at the emer­gence of a more-neg­a­tive tone from the agency’s pre­sen­ta­tion rel­a­tive to what was in­clud­ed with­in the FDA staff re­port post­ed two days pri­or, de­spite valid points made about the com­pa­ny’s risk mit­i­ga­tion plan.

Wil­ley wrote: “…the agency’s at­tempt to frame so­tagliflozin-me­di­at­ed DKA risk rel­a­tive to post-mar­ket­ing DKA events as­so­ci­at­ed with off-la­bel SGLT2i uti­liza­tion was in­her­ent­ly flawed. We’re not triv­i­al­iz­ing the risk here…How­ev­er, we do be­lieve the as­sump­tion of risk – par­tic­u­lar­ly for a drug which has sur­passed the re­quired ef­fi­ca­cy thresh­old in a dis­ease which has been ab­sent of in­no­va­tion since the ad­vent of in­sulin it­self – should be an in­di­vid­u­al­ized de­ci­sion made be­tween pa­tient/physi­cian…this same sto­ry has al­ready played out in the world of in­sulin pumps – where­by tran­si­tion­ing a type I di­a­betes pa­tient from in­jectable to pump-de­liv­ered in­sulin sig­nif­i­cant­ly in­creased DKA rates. Yet with suf­fi­cient pa­tient aware­ness/ed­u­ca­tion, these rates be­came man­age­able over time.”

Most an­a­lysts trimmed their ex­pec­ta­tions of the drug’s ap­proval for type I di­a­bet­ics.

Wil­ley said his mod­el still as­sumed a com­mer­cial launch in the US and EU in 2019, ac­knowl­edg­ing that the tim­ing was un­clear giv­en the re­sult of FDA pan­el meet­ing. He cut his 2021 US sales es­ti­mate to $245 mil­lion from $385 mil­lion. “If ap­proved, we still be­lieve this could prove to be a >$750M prod­uct in both the U.S. and EU with <12% mar­ket share amongst a grow­ing num­ber of type I di­a­bet­ic adults,” he not­ed.

Oth­er an­a­lysts were some­what more pes­simistic. Need­ham’s Alan Carr said he now be­lieves an FDA ap­proval in type I di­a­betes is pos­si­ble, but not prob­a­ble, and that he had elim­i­nat­ed the rev­enue stream from his mod­el. Cowen an­a­lysts, mean­while, were ready to throw in the tow­el, say­ing they now ex­pect an FDA re­jec­tion in March.

Lex­i­con’s shares $LXRX tum­bled about 25%, while Sanofi’s stock $SNY slipped about 1% in ear­ly trad­ing on Fri­day.

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