What Will It Take to Re­verse Fi­bro­sis in Pa­tients with Ad­vanced MASH?

Glucagon-like pep­tide-1 (GLP-1) re­cep­tor ag­o­nists have gained at­ten­tion as po­ten­tial treat­ments for a va­ri­ety of obe­si­ty-re­lat­ed dis­eases, in­clud­ing meta­bol­ic dys­func­tion-as­so­ci­at­ed steato­hep­ati­tis (MASH) and chron­ic kid­ney dis­ease. While these drugs are not yet ap­proved for these con­di­tions, their in­flu­ence on the meta­bol­ic sys­tem makes them wor­thy of study. How­ev­er, the meta­bol­ic sys­tem is com­plex, in­volv­ing nu­mer­ous path­ways that con­tribute to these dis­eases. In the case of MASH, the fi­brob­last growth fac­tor 21 (FGF21) sig­nal­ing path­way is par­tic­u­lar­ly sig­nif­i­cant.

MASH, for­mer­ly known as non­al­co­holic steato­hep­ati­tis (NASH), is a chron­ic and pro­gres­sive liv­er dis­ease char­ac­ter­ized by fat ac­cu­mu­la­tion, in­flam­ma­tion, and ul­ti­mate­ly fi­bro­sis—the scar­ring that re­sults from the liv­er’s at­tempts to re­pair dam­aged cells. This liv­er dam­age can progress to more se­vere com­pli­ca­tions, in­clud­ing cir­rho­sis, liv­er fail­ure and liv­er can­cer.¹ The num­ber of peo­ple im­pact­ed by MASH is stag­ger­ing, and the in­ci­dence is steadi­ly in­creas­ing. He­pa­tol­o­gists re­port that they now see young and mid­dle-aged peo­ple —those in their 30s and 40s—who have de­vel­oped ad­vanced liv­er dis­ease. By 2030, an es­ti­mat­ed² 27 mil­lion peo­ple in the Unit­ed States will have MASH, of whom 7.94 mil­lion will have ad­vanced fi­bro­sis (stages F3/F4).

Giv­en this ur­gent health con­cern, in­no­v­a­tive treat­ments for MASH are crit­i­cal­ly need­ed, es­pe­cial­ly ther­a­pies that can re­verse liv­er fi­bro­sis in late-stage pa­tients to pre­vent pro­gres­sion to cir­rho­sis, de­com­pen­sa­tion, or liv­er can­cer. Ac­tive med­ical in­ter­ven­tion is es­sen­tial for pa­tients with ad­vanced fi­bro­sis³. Ex­perts sug­gest that po­tent an­ti-fi­brot­ic agents like FGF21 analogs could of­fer sig­nif­i­cant ben­e­fits. One such agent is pe­gozafer­min, a nov­el in­ves­ti­ga­tion­al treat­ment cur­rent­ly in Phase 3 clin­i­cal de­vel­op­ment for pa­tients with MASH and MASH-re­lat­ed cir­rho­sis.

Pe­gozafer­min: En­cour­ag­ing re­sults show­ing the re­ver­sal of fi­bro­sis in a Phase 2 study

We be­lieve pe­gozafer­min ad­dress­es the dri­vers of MASH oc­cur­ring both with­in the liv­er—in­clud­ing ad­dress­ing fi­bro­sis, as well as sys­tem­i­cal­ly. As a specif­i­cal­ly en­gi­neered gly­coP­E­Gy­lat­ed ana­log of FGF21, it pro­longs the broad meta­bol­ic ef­fects of this en­doge­nous hor­mone. The ef­fects in­clude reg­u­lat­ing en­er­gy ex­pen­di­ture, im­prov­ing glu­cose and lipid me­tab­o­lism, and re­duc­ing fat with­in the liv­er—all cru­cial fac­tors in man­ag­ing MASH.

In our Phase 2b EN­LIV­EN tri­al with biop­sy-de­ter­mined F2/F3 fi­bro­sis due to MASH, pe­gozafer­min demon­strat­ed sig­nif­i­cant re­sults. Pa­tients re­ceiv­ing pe­gozafer­min achieved im­prove­ments in key non-in­va­sive mark­ers of fi­bro­sis, steato­sis and in­flam­ma­tion. Af­ter on­ly 24 weeks of treat­ment, pe­gozafer­min-treat­ed pa­tients achieved high­ly sta­tis­ti­cal­ly sig­nif­i­cant fi­bro­sis re­gres­sion with­out wors­en­ing of MASH on biop­sy, meet­ing the pri­ma­ry end­point in the study. Ad­di­tion­al­ly, pe­gozafer­min demon­strat­ed ad­di­tive ben­e­fits when used along­side back­ground GLP-1-based ther­a­pies, lead­ing to sus­tained im­prove­ments in liv­er health mark­ers.

An im­por­tant as­pect of pe­gozafer­min’s po­ten­tial pro­file is its fa­vor­able safe­ty and tol­er­a­bil­i­ty, which is cru­cial for a con­di­tion that may re­quire long-term treat­ment. Good tol­er­a­bil­i­ty en­hances pa­tient ad­her­ence, lead­ing to bet­ter clin­i­cal out­comes. Fur­ther­more, we are de­vel­op­ing pe­gozafer­min for self-ad­min­is­tra­tion as a sin­gle sub­cu­ta­neous in­jec­tion ei­ther week­ly or every oth­er week. This con­ve­nience is par­tic­u­lar­ly ben­e­fi­cial for pa­tients who may al­ready be man­ag­ing mul­ti­ple med­ica­tions due to co-ex­ist­ing health con­di­tions.

Ad­vanc­ing to Phase 3 clin­i­cal tri­als

Build­ing on the promis­ing re­sults from the Phase 2b tri­al, we ad­vanced pe­gozafer­min in­to two glob­al Phase 3 tri­als, both with po­ten­tial path­ways to ac­cel­er­at­ed ap­proval, fol­lowed by a po­ten­tial for full ap­proval:

• EN­LIGHT­EN-Fi­bro­sis: A ran­dom­ized, dou­ble-blind, place­bo-con­trolled study eval­u­at­ing pe­gozafer­min in pa­tients with MASH and fi­bro­sis (F2-F3).
• EN­LIGHT­EN-Cir­rho­sis: A sim­i­lar study fo­cus­ing on MASH pa­tients with com­pen­sat­ed cir­rho­sis (F4).

These reg­is­tra­tion-en­abling tri­als aim to fur­ther as­sess the ef­fi­ca­cy and safe­ty of pe­gozafer­min, bring­ing it one step clos­er to po­ten­tial ap­proval and avail­abil­i­ty for pa­tients in need.

Ad­vanc­ing a po­ten­tial main­stay treat­ment for MASH

Giv­en the com­plex­i­ty and mul­ti­fac­to­r­i­al na­ture of ad­vanced MASH, a com­pre­hen­sive treat­ment ap­proach is nec­es­sary. This in­cludes ther­a­pies that are not on­ly ef­fec­tive but al­so tol­er­a­ble and con­ve­nient, with the po­ten­tial to com­bine with oth­er ther­a­pies. Re­vers­ing fi­bro­sis is a crit­i­cal goal to re­duce the risk of liv­er-re­lat­ed events and over­all mor­tal­i­ty as the dis­ease pro­gress­es.

We be­lieve that pe­gozafer­min, if ap­proved, could be­come a best-in-class FGF21 ana­log ther­a­py and a cor­ner­stone treat­ment for pa­tients with ad­vanced fi­bro­sis and cir­rho­sis due to MASH. Its po­tent an­ti-fi­brot­ic ef­fects, meta­bol­ic ben­e­fits, fa­vor­able safe­ty pro­file, and user-friend­ly dos­ing sched­ule po­si­tion it as a promis­ing so­lu­tion to this press­ing med­ical chal­lenge.

Our com­mit­ment at 89bio is un­wa­ver­ing, as we strive to bring this in­no­v­a­tive po­ten­tial treat­ment to the mil­lions of pa­tients af­fect­ed by MASH, of­fer­ing hope for im­proved out­comes and qual­i­ty of life.

¹Bene­dict M, Zhang X. Non-al­co­holic fat­ty liv­er dis­ease: an ex­pand­ed re­view. World J He­pa­tol. 2017; 9:715-732. doi:10.4254/wjh.v9.i16.715.

²Estes C, Raza­vi H, Loom­ba R, Younos­si Z, Sanyal AJ. Mod­el­ing the epi­dem­ic of non­al­co­holic fat­ty liv­er dis­ease demon­strates an ex­po­nen­tial in­crease in bur­den of dis­ease. He­pa­tol­ogy. 2018;67(1):123-133. doi:10.1002/hep.29466.

³Da­jani A, AbuHam­mour A. Treat­ment of non­al­co­holic fat­ty liv­er dis­ease: Where do we stand? an overview. Sau­di J Gas­troen­terol. 2016;22(2):91-105. doi:10.4103/1319-3767.178527.