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.

UP­DAT­ED: In sur­prise switch, Bris­tol-My­ers is sell­ing off block­buster Ote­zla, promis­ing to com­plete Cel­gene ac­qui­si­tion — just lat­er

Apart from revealing its checkpoint inhibitor Opdivo blew a big liver cancer study on Monday, Bristol-Myers Squibb said its plans to swallow Celgene will require the sale of blockbuster psoriasis treatment Otezla to keep the Federal Trade Commission (FTC) at bay.

The announcement — which has potentially delayed the completion of the takeover to early 2020 — irked investors, triggering the New York-based drugmaker’s shares to tumble Monday morning in premarket trading.

Celgene’s Otezla, approved in 2014 for psoriasis and psoriatic arthritis, is a rising star. It generated global sales of $1.6 billion last year, up from the nearly $1.3 billion in 2017. Apart from the partial overlap of Bristol-Myers injectable Orencia, the company’s rival oral TYK2 psoriasis drug is in late-stage development, after the firm posted encouraging mid-stage data on the drug, BMS-986165, last fall. With Monday’s decision, it appears Bristol-Myers is favoring its experimental drug, and discounting Otezla’s future.

The move blindsided some analysts. Credit Suisse’s Vamil Divan noted just days ago:

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Novotech CEO Dr. John Moller

Novotech CRO Award­ed Frost & Sul­li­van Best Biotech CRO Asia-Pa­cif­ic 2019

Known in the in­dus­try as the Asia-Pa­cif­ic CRO, Novotech is now lead CRO ser­vices provider for the grow­ing num­ber of in­ter­na­tion­al biotechs se­lect­ing the re­gion for their stud­ies.

Re­flect­ing this Asia-Pa­cif­ic growth, Novotech staff num­bers are up 20% since De­cem­ber 2018 to 600 in-house clin­i­cal re­search peo­ple across a full range of ser­vices, across the re­gion.

Novotech’s ca­pa­bil­i­ties have been rec­og­nized by an­a­lysts like Frost & Sul­li­van, most re­cent­ly with the pres­ti­gious Asia-Pa­cif­ic CRO Biotech of the year award for best prac­tices in clin­i­cal re­search for biotechs for the fifth year. See oth­er awards here.

Fol­low­ing news of job cuts in Eu­ro­pean R&D ops, Sanofi con­firms it’s of­fer­ing US work­ers an 'ear­ly ex­it'

Ear­li­er in the week we learned that Sanofi was bring­ing out the bud­get ax to trim 466 R&D jobs in Eu­rope, re­tool­ing its ap­proach to car­dio as re­search chief John Reed beefed up their work in can­cer and gene ther­a­pies. And we’re end­ing the week with news that the phar­ma gi­ant has al­so been qui­et­ly re­duc­ing staff in the US, tar­get­ing hun­dreds of jobs as the com­pa­ny push­es vol­un­tary buy­outs with a fo­cus on R&D sup­port ser­vices.

Suf­fer­ing No­var­tis part­ner Cona­tus is pack­ing it in on NASH af­ter a se­ries of un­for­tu­nate tri­al events

The NASH par­ty is over at No­var­tis-backed Cona­tus. And this time they’re turn­ing off the lights.

More than 2 years af­ter No­var­tis sur­prised the biotech in­vest­ment com­mu­ni­ty with its $50 mil­lion up­front and promise of R&D sup­port to part­ner with the lit­tle biotech on NASH — ig­nit­ing a light­ning strike for the share price — Cona­tus $CNAT is back with the lat­est bit­ter tale to tell about em­ri­c­as­an, which once in­spired con­fi­dence at the phar­ma gi­ant.

Bris­tol-My­ers star Op­di­vo fails sur­vival test in a matchup with Nex­avar aimed at shak­ing up the big HCC mar­ket

Bris­tol-My­ers Squibb has suf­fered an­oth­er painful set­back in its years-long quest to ex­pand the reach of Op­di­vo. The phar­ma gi­ant this morn­ing not­ed that their Check­mate-459 study com­par­ing Op­di­vo with Bay­er’s Nex­avar in front­line cas­es of he­pa­to­cel­lu­lar car­ci­no­ma — the most com­mon form of liv­er can­cer — failed to hit the pri­ma­ry end­point on over­all sur­vival.

This was a sig­nif­i­cant mile­stone in Bris­tol-My­ers’ tal­ly of PD-1 cat­a­lysts this year. Nex­avar (so­rafenib) has been the stan­dard of care in front­line HCC for the past decade, though Op­di­vo has been mak­ing head­way in sec­ond-line HCC cas­es, where it’s go­ing toe-to-toe with Bay­er’s Sti­var­ga (re­go­rafenib) af­ter re­cent ap­provals shook up the mar­ket.

Bet­ter than Am­bi­en? Min­er­va soars on PhI­Ib up­date on sel­torex­ant for in­som­nia

A month af­ter roil­ing in­vestors with what skep­tics dis­missed as cher­ry pick­ing of its de­pres­sion da­ta, Min­er­va is back with a clean slate of da­ta from its Phase IIb in­som­nia tri­al.

In a de­tailed up­date, the Waltham, MA-based biotech said sel­torex­ant (MIN-202) hit both the pri­ma­ry and sev­er­al sec­ondary end­points, ef­fec­tive­ly im­prov­ing sleep in­duc­tion and pro­long­ing sleep du­ra­tion. In­ves­ti­ga­tors made a point to note that the ef­fects were con­sis­tent across the adult and el­der­ly pop­u­la­tions, with the lat­ter more prone to the sleep dis­or­der.

Gene ther­a­py biotech sees its stock rock­et high­er on promis­ing re­sults for rare cas­es of but­ter­fly dis­ease

Shares of Krys­tal Biotech took off this morn­ing $KRYS af­ter the lit­tle biotech re­port­ed promis­ing re­sults from its gene ther­a­py to treat a rare skin dis­ease called epi­der­mol­y­sis bul­losa.

Fo­cus­ing on an up­date with 4 new pa­tients, re­searchers spot­light­ed the suc­cess of KB103 in clos­ing some stub­born wounds. Krys­tal says that of 4 re­cur­ring and 2 chron­ic skin wounds treat­ed with the gene ther­a­py, the KB103 group saw the clo­sure of 5. The 6th — a chron­ic wound, de­fined as a wound that had re­mained open for more than 12 weeks — was par­tial­ly closed. That brings the to­tal so far to 8 treat­ed wounds, with 7 clo­sures.

Ab­b­Vie gets a green light to re­sume re­cruit­ing pa­tients for one myelo­ma study — but Ven­clex­ta re­mains un­der a cloud

Three months af­ter reg­u­la­tors at the FDA forced Ab­b­Vie to halt en­rolling pa­tients in its tri­als of a com­bi­na­tion us­ing Ven­clex­ta (vene­to­clax) to treat drug-re­sis­tant cas­es of mul­ti­ple myelo­ma, the agency has green-light­ed the re­sump­tion of one of those stud­ies, while keep­ing the rest on the side­lines.

The CANO­VA (M13-494) study can now get back in busi­ness re­cruit­ing pa­tients to test the drug for a pop­u­la­tion that shares a par­tic­u­lar ge­net­ic bio­mark­er. To get that per­mis­sion, Ab­b­Vie — which is part­nered with Roche on this pro­gram — was forced to re­vise the pro­to­col, mak­ing un­spec­i­fied changes in­volv­ing risk mit­i­ga­tion mea­sures, pro­to­col-spec­i­fied guide­lines and an up­dat­ed fu­til­i­ty cri­te­ria.

Dean Hum. Nasdaq via YouTube

Gen­fit goes to Chi­na with a deal worth up to $228M for NASH drug

Fresh off the high of its Nas­daq IPO de­but, and the low of com­par­isons to Cymabay — whose NASH drug re­cent­ly stum­bled — Gen­fit on Mon­day un­veiled an up to $228 mil­lion deal with transpa­cif­ic biotech Terns Phar­ma­ceu­ti­cals to de­vel­op its flag­ship ex­per­i­men­tal liv­er drug — elafi­bra­nor — in Greater Chi­na.

The deal comes more than a week af­ter Gen­fit $GN­FT is­sued a fiery de­fense of its dual PPAR ag­o­nist elafi­bra­nor, when com­peti­tor Cymabay’s PPARδ ag­o­nist, se­ladel­par, fiz­zled in a snap­shot of da­ta from an on­go­ing mid-stage tri­al. The main goal at the end of 12 weeks was for se­ladel­par to in­duce a sta­tis­ti­cal­ly sig­nif­i­cant im­prove­ment in liv­er fat con­tent, but da­ta showed that pa­tients on the place­bo ac­tu­al­ly per­formed bet­ter.