Evolv­ing Treat­ment Land­scape for NASH

Sev­er­al bio­phar­ma com­pa­nies are de­vel­op­ing treat­ments for non­al­co­holic steato­hep­ati­tis (NASH). Al­though some set­backs have oc­curred late­ly with dis­ap­point­ing da­ta, promis­ing da­ta is be­ing pre­sent­ed at the Amer­i­can As­so­ci­a­tion for the Study of Liv­er Dis­ease’s (AASLD) Liv­er Meet­ing. Dr. Ro­hit Loom­ba, an in­ter­na­tion­al­ly-renowned ex­pert in NASH, an­swers press­ing ques­tions and dis­cuss­es re­search on 89bio’s in­ves­ti­ga­tion­al treat­ment, for which he serves on the Steer­ing Com­mit­tee of a mid-stage clin­i­cal tri­al. He is the Di­rec­tor of the UC San Diego NAFLD Re­search Cen­ter and Di­rec­tor of He­pa­tol­ogy at UC San Diego School of Med­i­cine.

Dr. Ro­hit Loom­ba, Di­rec­tor of the UC San Diego NAFLD Re­search Cen­ter and Di­rec­tor of He­pa­tol­ogy at UC San Diego School of Med­i­cine

What is NASH and why should we be con­cerned about it?

Dr. Loom­ba: NASH is a chron­ic, pro­gres­sive dis­ease in which ex­cess fat builds up in the liv­er, caus­ing in­flam­ma­tion, liv­er cell in­jury and fi­bro­sis (scar­ring). Most pa­tients ex­pe­ri­ence few or no symp­toms un­til the very late stage. As a re­sult, the dis­ease pro­gress­es un­de­tect­ed for years or even decades, dam­ag­ing the liv­er and lead­ing to se­vere liv­er-re­lat­ed com­pli­ca­tions, in­clud­ing cir­rho­sis, which af­fects 15% to 20% of pa­tients, liv­er fail­ure and he­pa­to­cel­lu­lar can­cer (HCC). NASH-re­lat­ed cir­rho­sis and HCC are now the sec­ond lead­ing caus­es of liv­er trans­plan­ta­tion in the Unit­ed States and are ex­pect­ed to be­come the lead­ing caus­es in the com­ing decade.

NASH is in­creas­ing in preva­lence large­ly due to the obe­si­ty epi­dem­ic and the rise in preva­lence of Type 2 di­a­betes, in­sulin re­sis­tance and meta­bol­ic syn­drome.

What is the cur­rent treat­ment for NASH and why has this dis­ease been so dif­fi­cult to ad­dress?

Dr. Loom­ba: Cur­rent­ly, no med­i­cines are ap­proved by the FDA to treat NASH, and pa­tients must re­ly on treat­ment of co-mor­bidi­ties and lifestyle changes, in­clud­ing di­et and ex­er­cise to in­duce weight loss, and im­prove­ment of glycemic con­trol with di­et, ex­er­cise and med­ica­tions in those with di­a­betes. Be­cause NASH is a com­plex dis­ease and its pro­gres­sion is thought to be mul­ti­fac­to­r­i­al, treat­ment ap­proach­es re­quire tar­get­ing dif­fer­ent un­der­ly­ing patholo­gies. Sev­er­al agents are in var­i­ous stages of clin­i­cal tri­als; one promis­ing ap­proach in­volves tar­get­ing FGF21.

Tell us more about FGF21. Why do you think FGF21 could be the best treat­ment modal­i­ty mov­ing for­ward?

Dr. Loom­ba: Fi­brob­last growth fac­tor 21 (FGF21) is an en­docrine hor­mone that reg­u­lates glu­cose, lipid me­tab­o­lism and en­er­gy ex­pen­di­ture. Clin­i­cal stud­ies have shown that FGF21 re­duces liv­er fat and im­pacts liv­er fi­bro­sis, sug­gest­ing it could im­prove the liv­er and meta­bol­ic ab­nor­mal­i­ties as­so­ci­at­ed with NASH. FGF21 is unique in that, in ad­di­tion to ad­dress­ing the liv­er man­i­fes­ta­tions, it works on the mul­ti­ple co-mor­bidi­ties that wors­en NASH, such as high triglyc­erides and in­sulin re­sis­tance. Three FGF21 ana­log pro­grams are in Phase 2 clin­i­cal tri­als, in­clud­ing BIO89-100, which is specif­i­cal­ly en­gi­neered us­ing gly­coP­E­Gy­lat­ed tech­nol­o­gy to pro­long the bi­o­log­i­cal ac­tiv­i­ty of FGF21.

Re­sults from a clin­i­cal tri­al of BIO89-100 are be­ing pre­sent­ed this week­end at The Liv­er Meet­ing. Can you tell us about the find­ings and why the da­ta are sig­nif­i­cant?

Dr. Loom­ba: Re­sults from the Phase 1b/2a clin­i­cal tri­al of BIO89-100 in pa­tients with NASH will be pre­sent­ed as a late-break­er. This ran­dom­ized, dou­ble-blind, place­bo-con­trolled, mul­ti­ple as­cend­ing dose-rang­ing study en­rolled 81 pa­tients. The da­ta to be pre­sent­ed showed that BIO89-100 had strong ef­fi­ca­cy and fa­vor­able tol­er­a­bil­i­ty with week­ly and every two-week sub­cu­ta­neous dos­ing.

Pa­tients treat­ed with BIO89-100 for 12 weeks had ro­bust re­duc­tions in liv­er fat, as mea­sured by MRI-PDFF, and key liv­er mark­ers of in­jury, in­sulin re­sis­tance and serum bio­mark­ers of fi­bro­sis ver­sus those in the place­bo group. Specif­i­cal­ly, pa­tients treat­ed with BIO89-100 saw up to 70% re­duc­tion in liv­er fat ver­sus place­bo, with 43% of pa­tients at the high­est dose of BIO89-100 achiev­ing nor­mal liv­er fat con­tent of <5%. A re­spon­der analy­sis showed up to 88% of pa­tients treat­ed with BIO89-100 achieved ≥30% MRI-PDFF liv­er fat re­duc­tion, and up to 71% achieved ≥50% re­duc­tion in liv­er fat. These rates of rel­a­tive re­duc­tions in liv­er fat have been cor­re­lat­ed with liv­er his­tol­ogy ben­e­fits, in­clud­ing NASH res­o­lu­tion and NASH im­prove­ment. BIO89-100 al­so demon­strat­ed a sta­tis­ti­cal­ly sig­nif­i­cant ben­e­fit in key bio­mark­ers of liv­er in­jury, with re­duc­tions of up to 44% in ala­nine amino­trans­ferase (ALT), which has al­so been shown to cor­re­late with im­prove­ments in his­tol­ogy in NASH. Key lipid pa­ra­me­ters, in­clud­ing triglyc­erides and non-HDL and LDL cho­les­terol, sig­nif­i­cant­ly im­proved in the BIO89-100 treat­ment groups.

BIO89-100 had a fa­vor­able safe­ty and tol­er­a­bil­i­ty pro­file and was well tol­er­at­ed across the broad dose range test­ed in this study. In­creased ap­petite, an ad­verse event seen with FGF21 analogs, was the on­ly treat­ment-re­lat­ed ad­verse event oc­cur­ring in ≥10% of pooled BIO89-10 pa­tients. Ad­di­tion­al­ly, BIO89-100 had a GI tol­er­a­bil­i­ty pro­file sim­i­lar to place­bo.

These find­ings add to a grow­ing body of ev­i­dence demon­strat­ing the po­ten­tial of BIO89-100 for the treat­ment of NASH. The da­ta high­light the promis­ing clin­i­cal pro­file of BIO89-100 and its po­ten­tial to be one of the lead­ing FGF21 analogs in a class that could po­ten­tial­ly be­come a key com­po­nent of the treat­ment par­a­digm in NASH.

Why is BIO89-100 promis­ing in NASH?

Dr. Loom­ba: In ad­di­tion to ro­bust ef­fi­ca­cy da­ta, BIO89-100 is as­so­ci­at­ed with few GI ad­verse events. Low rates of di­ar­rhea and nau­sea and no vom­it­ing were re­port­ed in the Phase 1b/2a tri­al. Min­i­miz­ing GI ad­verse events is im­por­tant in a con­di­tion re­quir­ing chron­ic treat­ment, as poor GI tol­er­a­bil­i­ty could ad­verse­ly af­fect pa­tients’ qual­i­ty of life, ad­her­ence to treat­ment, and clin­i­cal out­comes. BIO89-100 can be dosed ei­ther week­ly or every two weeks. Of­fer­ing pa­tients a well-tol­er­at­ed med­i­cine with a less fre­quent dos­ing sched­ule will be im­por­tant be­cause NASH is chron­ic and of­ten asymp­to­matic, and com­pli­ance will be im­por­tant for long-term ben­e­fits.

What’s next for this in­ves­ti­ga­tion­al treat­ment?

Dr. Loom­ba: These re­sults sup­port ad­vanc­ing a com­pre­hen­sive clin­i­cal de­vel­op­ment pro­gram for BIO89-100 in NASH to en­able quick pro­gres­sion in­to as­sess­ment of liv­er his­to­log­ic end­points in a Phase 2b tri­al as part of a po­ten­tial Phase 2b/3 pro­gram. That tri­al is planned to start in the first half of next year, and an ex­pan­sion co­hort in the Phase 1b/2a study is planned in the near-term to gen­er­ate his­tol­ogy da­ta in pa­tients with NASH.

Learn more about 89bio and its de­vel­op­ment of BIO89-100 in NASH here.