FDA is­sues draft guid­ance on NASH drug de­vel­op­ment

The FDA on Mon­day is­sued draft guid­ance on de­vel­op­ing drugs to treat pa­tients who have non­cir­rhot­ic non­al­co­holic steato­hep­ati­tis (NASH) with liv­er fi­bro­sis.

“Cur­rent­ly, there are no ap­proved drugs for the treat­ment of NASH. Giv­en the high preva­lence of NASH, the as­so­ci­at­ed mor­bid­i­ty, the grow­ing bur­den of end-stage liv­er dis­ease, and the lim­it­ed avail­abil­i­ty of liv­ers for or­gan trans­plan­ta­tion, FDA be­lieves that iden­ti­fy­ing ther­a­pies that will slow the progress or, halt, or re­verse NASH and NAFLD will ad­dress an un­met med­ical need,” FDA writes.

How­ev­er, FDA ac­knowl­edges that there are knowl­edge gaps that present chal­lenges to de­vel­op­ing drugs to treat NASH. One par­tic­u­lar chal­lenge is that there are cur­rent­ly no cri­te­ria for iden­ti­fy­ing which pa­tients with non­al­co­holic fat­ty liv­er (NAFL) will progress to NASH.

Be­cause of this, FDA says that spon­sors should fo­cus on de­vel­op­ing treat­ments non­cir­rhot­ic NASH with liv­er fi­bro­sis un­til there are meth­ods for iden­ti­fy­ing the sub­set of pa­tients who are at risk of pro­gres­sion.

FDA al­so en­cour­ages spon­sors to de­vel­op and val­i­date bio­mark­ers for di­ag­nos­ing and grad­ing NASH and liv­er fi­bro­sis, as liv­er biop­sy is cur­rent­ly the on­ly re­li­able method for di­ag­nos­ing the dis­ease.


The guid­ance it­self pro­vides rec­om­men­da­tions for pre­clin­i­cal and clin­i­cal de­vel­op­ment as well as tri­al de­sign and end­point se­lec­tion to sup­port ap­proval of drugs to treat non­cir­rhot­ic NASH with liv­er fi­bro­sis.

FDA notes that the guid­ance is not meant to cov­er the de­vel­op­ment of drugs to treat cir­rho­sis caused by NASH or the de­vel­op­ment of in vit­ro di­ag­nos­tics that may be used in de­vel­op­ing drugs to treat the dis­ease.

For Phase 3 stud­ies, FDA says that spon­sors should en­roll pa­tients with a his­to­log­i­cal di­ag­no­sis of NASH with liv­er fi­bro­sis made with­in six months of en­roll­ment, tak­ing in­to con­sid­er­a­tion pa­tients’ stan­dard of care and back­ground ther­a­py for oth­er chron­ic con­di­tions. FDA al­so says that pa­tients’ weight should be sta­ble for three months pri­or to en­roll­ment.

FDA al­so says that Phase 3 stud­ies for NASH should be dou­ble-blind and place­bo-con­trolled with the goal of slow­ing, halt­ing or re­vers­ing dis­ease pro­gres­sion and im­prov­ing clin­i­cal out­comes.

“Be­cause of the slow pro­gres­sion of NASH and the time re­quired to con­duct a tri­al that would eval­u­ate clin­i­cal end­points such as pro­gres­sion to cir­rho­sis or sur­vival, the FDA rec­om­mends spon­sors con­sid­er … liv­er his­to­log­i­cal im­prove­ments as end­points rea­son­ably like­ly to pre­dict clin­i­cal ben­e­fit to sup­port ac­cel­er­at­ed ap­proval,” FDA writes.

Those end­points in­clude res­o­lu­tion of steato­hep­ati­tis on over­all histopatho­log­i­cal read­ing and no wors­en­ing of liv­er fi­bro­sis on NASH Clin­i­cal Re­search Net­work (CRN) fi­bro­sis score and/or im­prove­ment in liv­er fi­bro­sis greater than or equal to one stage (NASH CRN fi­bro­sis score) and no wors­en­ing of steato­hep­ati­tis.

For NASH treat­ments grant­ed ac­cel­er­at­ed ap­proval on the ba­sis of liv­er his­tol­ogy, FDA says that ran­dom­ized, dou­ble-blind, place­bo-con­trolled tri­als to ver­i­fy clin­i­cal ben­e­fits should be un­der­way when the mar­ket­ing ap­pli­ca­tion is sub­mit­ted.

The guid­ance al­so pro­vides some caveats for pe­di­atric de­vel­op­ment, as “Pe­di­atric NASH ap­pears to have dif­fer­ent his­to­log­i­cal char­ac­ter­is­tics as well as a dif­fer­ent nat­ur­al his­to­ry when com­pared to adult NASH. For rea­sons that are cur­rent­ly un­known, dis­ease char­ac­ter­is­tics and pro­gres­sion in pe­di­atric pa­tients may be dif­fer­ent.”

As such, FDA says that ex­trap­o­la­tion of ef­fi­ca­cy from adults “is not ap­pro­pri­ate at this time,” and that lon­gi­tu­di­nal nat­ur­al his­to­ry da­ta for pe­di­atric pa­tients are need­ed.

FDA says it plans to fur­ther ad­dress is­sues re­lat­ed to pe­di­atric non­cir­rhot­ic NASH in an up­com­ing guid­ance.

Draft Guid­ance, Fed­er­al Reg­is­ter No­tice

First pub­lished here. Reg­u­la­to­ry Fo­cus is the flag­ship on­line pub­li­ca­tion of the Reg­u­la­to­ry Af­fairs Pro­fes­sion­als So­ci­ety (RAPS), the largest glob­al or­ga­ni­za­tion of and for those in­volved with the reg­u­la­tion of health­care and re­lat­ed prod­ucts, in­clud­ing med­ical de­vices, phar­ma­ceu­ti­cals, bi­o­log­ics and nu­tri­tion­al prod­ucts. Email news@raps.org for more in­for­ma­tion.

From left to right: Lilian Kim, Associate Director Business Development; John Moller, CEO; Yooni Kim, Executive Director, Asia Operations; Michelle Park, Director South Korea Operations.

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A preda­tor's world? Top an­a­lyst sees the 'haves' and the 'haven't­s' di­verge as biotech bub­bles form — and col­lapse

Josh Schimmer

We’ve all seen the deluge of cash that’s been pouring into biotech from every angle: VCs, IPOs and follow-ons have generated billions in capital for new and emerging drug developers with ready access to some powerful new tech. But Evercore ISI’s Josh Schimmer is asking where we’re headed from here.

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Pfizer, South San Francisco — Jeff Rumans for Endpoints News

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Count Pfizer in as a top player in the blockbuster game of JAK1 inhibitors.

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As of now, Pfizer looks to be equipped to run into the review stage — advantaged by a breakthrough therapy designation that is intended to speed up the regulatory process.

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In 2006, Shinya Yamanaka shook stem cell research with his discovery that mature cells can be converted into stem cells, relieving a longstanding political-ethical blockage and throwing open medical research on everything from curbing eye degeneration to organ printing.

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Hal Barron and Rick Klausner (GSK, Lyell)

Ex­clu­sive: GSK’s Hal Bar­ron al­lies with Rick Klaus­ner’s $600M cell ther­a­py start­up, look­ing to break new ground blitz­ing sol­id tu­mors

LONDON — Chances are, you’ve heard little or nothing about Rick Klausner’s startup Lyell. But that ends now.

Klausner, the former head of the National Cancer Institute, former executive director for global health at the Gates Foundation, co-founder at Juno and one of the leaders in the booming cell therapy field, has brought together one of the most prominent teams of scientists tackling cell therapy 2.0 — highlighted by a quest to bridge a daunting tech gap that separates some profound advances in blood cancers with solid tumors. And today he’s officially adding Hal Barron and GlaxoSmithKline as a major league collaborator which is pitching in a large portion of the $600 million he’s raised in the past year to make that vision a reality.

“We’ve being staying stealth,” Klausner tells me, then adding with a chuckle: “and going back to stealth after this.”

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Patrick Mahaffy, Getty Images

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The bottom line:

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