Lit­tle Cona­tus' No­var­tis-part­nered liv­er drug suf­fers third straight de­feat, but CEO Men­to is still hold­ing out hope

Lit­tle Cona­tus’ No­var­tis-part­nered liv­er drug is one step clos­er to the scrap heap, with its third mid-stage fail­ure.

The Swiss drug­mak­er hand­ed the San Diego-based biotech $50 mil­lion up­front and an in­jec­tion of con­fi­dence in late 2016 to li­cense the drug, em­ri­c­as­an. Since then, it has flopped in a tri­fec­ta of stud­ies. An­oth­er Phase II study is ex­pect­ed to read­out lat­er this year.

Steven Men­to

The 318-pa­tient tri­al, dubbed EN­CORE-NF, was test­ing two dos­es (5 mg, 50 mg) of the drug against a place­bo in biop­sy-con­firmed NASH and liv­er fi­bro­sis pa­tients. Em­ri­c­as­an missed the pri­ma­ry end­point of im­prov­ing fi­bro­sis by ≥1 on the val­i­dat­ed Clin­i­cal Re­search Net­work (CRN) stage sys­tem, with no wors­en­ing of steato­hep­ati­tis com­pared to place­bo at week 72, the com­pa­ny said late Thurs­day.

In a sep­a­rate fil­ing, Cona­tus pro­vid­ed a lit­tle more tri­al de­tail. The re­sponse rates in the 5 mg em­ri­c­as­an, 50 mg em­ri­c­as­an and place­bo treat­ment groups were 11.2%, 12.3% and 19.0%, re­spec­tive­ly. Sta­tis­ti­cal­ly sig­nif­i­cant re­duc­tions were ob­served in ALT (el­e­vat­ed lev­els of this en­zyme in­di­cates a liv­er in dis­tress) and Cas­pase 3/7 (en­zymes that play es­sen­tial roles in pro­grammed cell death) in the 5 mg and 50 mg em­ri­c­as­an treat­ment groups.

The com­pa­ny’s shares $CNAT more than halved pre-mar­ket on Fri­day to $1.43.

Akin to the pre­vi­ous fail­ures, Cona­tus’ CEO played it cool, sug­gest­ing the drug could still work in pa­tients with NASH, which is typ­i­cal­ly as­so­ci­at­ed with obe­si­ty and di­a­betes and is set to eclipse he­pati­tis C as the lead­ing rea­son for liv­er trans­plants by 2020.

“Al­though em­ri­c­as­an did not have the de­sired ef­fect in these ear­li­er-stage NASH fi­bro­sis pa­tients, we be­lieve its demon­strat­ed bio­mark­er ac­tiv­i­ty across a broad spec­trum of liv­er dis­ease war­rants con­tin­ued eval­u­a­tion in more ad­vanced-stage NASH cir­rho­sis pa­tients,” chief Steven Men­to said in a state­ment, adding that the com­pa­ny would await ad­di­tion­al da­ta read­outs lat­er this year be­fore de­ter­min­ing the next steps for the em­ri­c­as­an pro­gram with No­var­tis.

Stifel’s Stephen Wil­ley did not buy what Cona­tus was sell­ing. “The fail­ure…fur­ther lim­its our abil­i­ty to gen­er­ate any lin­ger­ing en­thu­si­asm for re­main­ing full year 2019 mile­stones.”

“The lim­it­ed ef­fi­ca­cy de­tails pro­vid­ed by man­age­ment ac­tu­al­ly sug­gest­ed a di­rec­tion­al detri­ment in em­ri­c­as­an-treat­ed pa­tients…the lack of any clin­i­cal con­se­quences as­so­ci­at­ed with these ben­e­fits is con­sis­tent with every oth­er em­ri­c­as­an study re­port­ed to date.”

Last April, em­ri­c­as­an failed its first Phase II tri­al, in­volv­ing liv­er trans­plant pa­tients with fi­bro­sis or cir­rho­sis. In De­cem­ber, the drug failed to im­press in a sec­ond study (dubbed EN­CORE-PH), in­volv­ing NASH cir­rho­sis pa­tients — whose liv­ers were cop­ing with the dam­age and still able to per­form im­por­tant func­tions, but were at high risk for de­com­pen­sa­tion.

Wil­ley pre­dict­ed the Phase IIb EN­CORE-LF tri­al, slat­ed for read­out in mid-2019 and in­volv­ing de­com­pen­sat­ed NASH pa­tients, is al­so doomed to fail, giv­en that the 5/25mg em­ri­c­as­an dos­es giv­en in EN­CORE-PH ac­tu­al­ly re­sult­ed in wors­en­ing of symp­toms in pa­tients with base­line de­com­pen­sat­ed cir­rho­sis.

“(T)he on­ly em­ri­c­as­an dose with­in EN­CORE-PH to sug­gest an in­cre­men­tal ben­e­fit in de­com­pen­sat­ed pa­tients was the 50mg dose – which isn’t even be­ing eval­u­at­ed in EN­CORE-LF. We al­so be­lieve EN­CORE-LF-el­i­gi­ble pa­tients rep­re­sent a very dif­fi­cult-to-treat pop­u­la­tion of pa­tients in whom the na­ture and rate of events are of­ten both dif­fi­cult to pre­dict and un­cor­re­lat­ed to sup­port­ive care ther­a­py – mak­ing the achieve­ment of a sta­tis­ti­cal win in this set­ting an even more-chal­leng­ing en­deav­or.”

NASH — char­ac­ter­ized by a buildup of ex­cess fat in the liv­er that in­duces chron­ic in­flam­ma­tion and even­tu­al­ly cul­mi­nates in scar­ring that can lead to cir­rho­sis, liv­er fail­ure, can­cer and death — is a high risk-re­ward dis­ease that has at­tract­ed a pletho­ra of drug­mak­ers big and small, and re­searchers ex­pect it will take a cock­tail of new drugs to tru­ly de­feat the dis­ease.

In­ter­cept $ICPT in Feb­ru­ary re­port­ed that a piv­otal late-stage study test­ing its OCA treat­ment hit a high­ly sta­tis­ti­cal­ly sig­nif­i­cant score on an im­prove­ment in liv­er fi­bro­sis with­out any wors­en­ing of NASH, but missed the end­point for NASH res­o­lu­tion with­out wors­en­ing of fi­bro­sis. Gilead $GILD, mean­while, ex­pe­ri­enced a ma­jor set­back af­ter its NASH drug selon­sert­ib failed its Phase III. France’s Gen­fit is ex­pect­ed to of­fer its key NASH read­out lat­er this year.

Up­dat­ed: FDA re­mains silent on or­phan drug ex­clu­siv­i­ty af­ter last year's court loss

Since losing a controversial court case over orphan drug exclusivity last year, the FDA’s Office of Orphan Products Development has remained entirely silent on orphan exclusivity for any product approved since last November, leaving many sponsors in limbo on what to expect.

That silence means that for more than 70 orphan-designated indications for more than 60 products, OOPD has issued no public determination on the seven-year orphan exclusivity in the Orange Book, and no new listings of orphan exclusivity appear in OOPD’s searchable database, as highlighted recently by George O’Brien, a partner in Mayer Brown’s Washington, DC office.

Illustration: Assistant Editor Kathy Wong for Endpoints News

As mon­ey pours in­to dig­i­tal ther­a­peu­tics, in­sur­ance cov­er­age crawls



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