The Cen­ter for Drug Eval­u­a­tion and Re­search (CDER) at the FDA is­sued draft rec­om­men­da­tions for spon­sors look­ing to de­vel­op drugs to treat non­al­co­holic steato­hep­ati­tis (NASH) with com­pen­sat­ed cir­rho­sis.

NASH is as­so­ci­at­ed with a range of com­mon dis­eases, in­clud­ing type 2 di­a­betes, hy­per­ten­sion and obe­si­ty, among oth­ers. “It is a grow­ing pub­lic health con­cern and is an­tic­i­pat­ed to be the lead­ing cause of liv­er trans­plan­ta­tion with­in a decade,” the agency says. But “no stan­dard treat­ment ex­ists for NASH.”

The guid­ance fol­lows a sep­a­rate draft guid­ance is­sued in De­cem­ber that pro­vides rec­om­men­da­tions for ear­ly NASH drug de­vel­op­ment and de­vel­op­ing drugs to treat non­cir­rhot­ic NASH.

Guid­ance

To aid spon­sors of drugs to treat com­pen­sat­ed NASH cir­rho­sis dur­ing clin­i­cal de­vel­op­ment, the draft guid­ance de­tails the agency’s cur­rent rec­om­men­da­tions re­gard­ing com­po­nents of Phase III pro­grams.

Specif­i­cal­ly, the guid­ance de­tails pa­tient en­roll­ment cri­te­ria, clin­i­cal tri­al de­sign, ef­fi­ca­cy end­points and safe­ty con­sid­er­a­tions for Phase III tri­als.

The FDA em­phases that spon­sors should on­ly en­roll pa­tients in Phase III clin­i­cal tri­als whose cir­rho­sis is sec­ondary to NASH and should rule out oth­er caus­es of chron­ic liv­er dis­ease, such as al­co­holic liv­er dis­ease, vi­ral he­pati­tis and Wil­son’s dis­ease.

The guid­ance al­so pro­vides rec­om­men­da­tions for di­ag­nos­ing pa­tients with com­pen­sat­ed cir­rho­sis and for ex­clud­ing pa­tients with de­com­pen­sat­ed cir­rho­sis, among oth­er en­roll­ment cri­te­ria.

The FDA says that spon­sors should eval­u­ate drugs to treat com­pen­sat­ed NASH cir­rho­sis in ran­dom­ized, place­bo-con­trolled, dou­ble-blind clin­i­cal tri­als, and rec­om­mends that spon­sors should dis­cuss pro­posed strat­i­fi­ca­tion fac­tors with the agency be­fore be­gin­ning Phase III tri­als.

For ef­fi­ca­cy end­points, the FDA says spon­sors should “eval­u­ate the ef­fect of the in­ves­ti­ga­tion­al drug rel­a­tive to place­bo on the com­pos­ite end­point of time from ran­dom­iza­tion to the first of any one of” six out­comes, in­clud­ing com­pli­ca­tion of as­cites, variceal he­m­or­rhage, he­pat­ic en­cephalopa­thy, wors­en­ing in the Mod­el for End-State Liv­er Dis­ease (MELD) score, liv­er trans­plan­ta­tion or death from any cause.

The agency says it “strong­ly rec­om­mends clin­i­cal out­come tri­als to sup­port a mar­ket­ing ap­pli­ca­tion.” Yet a drug for the treat­ment of NASH cir­rho­sis will like­ly un­der­go FDA eval­u­a­tion through the tra­di­tion­al ap­proval path­way due to a cur­rent lack of ev­i­dence to sup­port an FDA ac­cel­er­at­ed ap­proval.

Draft guid­ance

First pub­lished in Reg­u­la­to­ry Fo­cus™ by the Reg­u­la­to­ry Af­fairs Pro­fes­sion­als So­ci­ety, the largest glob­al or­ga­ni­za­tion of and for those in­volved with the reg­u­la­tion of health­care prod­ucts. Click here for more in­for­ma­tion.

Im­age: An­drew Harnik AP

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.

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.

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.

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.

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.

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.

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.

→ Alex­ion $ALXN has scored a speedy re­view for Ul­tomiris for pa­tients with atyp­i­cal he­molyt­ic ure­mic syn­drome (aHUS) af­ter post­ing pos­i­tive da­ta from a piv­otal study in Jan­u­ary. The drug is the rare dis­ease com­pa­ny’s shot at pro­tect­ing its block­buster blood dis­or­der fran­chise that is cur­rent­ly cen­tered around its flag­ship drug, Soliris, which is a com­ple­ment in­hibitor typ­i­cal­ly ad­min­is­tered every two weeks. Ul­tomiris has a sim­i­lar mech­a­nism of ac­tion but re­quires less-fre­quent dos­ing — every eight weeks. The de­ci­sion date has been set to Oc­to­ber 19. Late last year, Ul­tomiris se­cured ap­proval for noc­tur­nal he­mo­glo­bin­uria (PNH) pa­tients.