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.

Guid­ance

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.

Lessons for biotech and phar­ma from a doc­tor who chased his own cure

After being struck by a rare disease as a healthy third year medical student, David Fajgenbaum began an arduous journey chasing his own cure. Amidst the hustle of this year’s JP Morgan conference, the digital trials platform Medable partnered with Endpoints Studio to share Dr. Fajgenbaum’s story with the drug development industry.

What follows is an edited transcript of the conversation between Medable CEO Dr. Michelle Longmire and Dr. Fajgenbaum, and it is full of lessons for biotech executives charged with bringing the next generation of medicines to patients.

Christos Kyratsous (via LinkedIn)

He built a MERS treat­ment in 6 months and then the best Ebo­la drug. Now Chris­tos Kyrat­sous turns his sights on Covid-19

TARRYTOWN, NY — In 2015, as the Ebola epidemic raged through swaths of West Africa, Kristen Pascal’s roommates sat her down on their couch and staged an intervention.

“Are you sure this is what you want to be doing with your life?” she recalls them asking her.

Pascal, a research associate for Regeneron, had been coming home at 2 am and leaving at 6 am. At one point, she didn’t see her roommate for a week. For months, that was life in Christos Kyratsous’ lab as the pair led a company-wide race to develop the first drug that could effectively treat Ebola before the outbreak ended. For Pascal, that was worth it.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 72,400+ biopharma pros reading Endpoints daily — and it's free.

Left to right, top to bottom: Carl Gordon, Adam Stone, Peter Moglia, David Schenkein, Robert Nelsen, Carol Gallagher; Srinivas Akkaraju, Ray Debbane, Jim Flynn, Peter Kolchinsky, Thilo Schroeder, Brad Bolzon

UP­DAT­ED: The top 100 bio­phar­ma ven­ture in­vestors at the mega­bil­lions deal ta­ble

The VC crowd took a step back last year, but nevertheless maintained a furious pace of new investments in therapeutic tech platforms and biotech startups. And the top 100 players completely dominated the megabillions game.

Just looking at the number of deals done by each of the top 100, OrbiMed came in at the top, with 20, followed by Alexandria (18), Perceptive (16) and the ubiquitous RA Capital at 16. It’s impossible to say exactly how much they invested in total — those numbers are only rarely provided — but it is clear from the numbers assembled by Chris Dokomajilar at DealForma who’s most likely to be found sitting at the table during the go-go days of biotech investing.

Dokomajilar tracked $14.06 billion in biotech venture investing last year, a dip from the frenzied pace of $16.02 billion in 2018 and more than $10 billion higher than he recorded for 2010, as the economy was recovering from a profound economic crisis.

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

Rahul Ballal, Imara

As sick­le cell pa­tients find new op­tions, NEA-found­ed Imara pitch­es mid-stage al­ter­na­tive for $86M IPO

November 2019 proved to be a fruitful month for patients with blood disorders known as hemoglobinopathies. Within days, the FDA ushered two drugs for sickle cell disease and another for beta thalassemia to the market — livening up a barren field.

Imara, a relatively young plower, is riding on that enthusiasm as it shoots for an $86.25 million IPO.

Imara emerged from New Enterprise Associates’ orphan drug accelerator Cydan in 2016 as a single-product company. $77.3 million in private financing later IMR-687 remains the sole asset in its pipeline; the difference is the drug is now in Phase II for sickle cell disease, with topline data slated for later this year and two other mid-stage beta thalassemia studies lined up.

RA joins glob­al syn­di­cate to back a $98M round for CAN­bridge

A Beijing-based rare disease and oncology player has raised $98 million to help fund the expansion of its pipeline as well as a commercial portfolio.

CANbridge put out word Tuesday that the global private equity player General Atlantic joined forces with Chinese CRO Wuxi AppTec to lead the Series D, with both ready to chip in an extra $10 million each under the right conditions. The syndicate includes RA Capital Management, Hudson Bay Capital Management, YuanMing Prudence Fund and Tigermed.

Carol Robinson, Professor Dame Carol Robinson Research Group

UP­DAT­ED: Drug dis­cov­ery in HD: Ox­ford spin­of­f's mass spec­trom­e­try ap­proach scores fresh fund­ing

The technology used to detect explosives at airports — mass spectrometry — is being piloted as an engine for drug discovery.

Mass spectrometry is a tool designed to measure with profound accuracy the mass of a single molecule. Typically, mass spectrometers can be used to identify unknown compounds, to quantify known compounds, and to determine the structure and chemical properties of molecules.

UP­DAT­ED: Chi­na ap­proves flu drug be­ing tout­ed as a po­ten­tial coro­n­avirus treat­ment amid a rush of clin­i­cal stud­ies

One of the three drugs that China’s Ministry of Science and Technology has tapped as potential COVID-19 treatments to watch has notched its first Chinese OK — for the flu.

While there’s no proof yet that fapilavir, or favipiravir, is the cure that patients and physicians are yearning for, it stands out for a unique constellation of qualities. It’s been commercially available in Japan for several years (unlike Gilead’s experimental remdesivir) yet it’s new to China (unlike the malaria drug chloroquine phosphate). Perhaps more importantly, a domestic biotech — Zhejiang Hisun Pharma — owns the rights to manufacture and market the drug, preempting any concerns about patents.

FDA goes on high alert as coro­n­avirus rais­es threat to drug man­u­fac­tur­ing and clin­i­cal tri­als grind to a halt

The FDA isn’t quite sure just what the coronavirus outbreak in China will mean for the US pharma industry, but it has the potential to trigger a host of troublesome issues around the supply chain the country is directly plugged into.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 72,400+ biopharma pros reading Endpoints daily — and it's free.

Warren Buffett, AP Images

War­ren Buf­fett gets a dou­ble take as the in­vest­ment pow­er­house set­tles on its first biotech in­vest­ment

Coke. American-Express. Apple. And Biogen?

Warren Buffet’s Berkshire Hathaway, which made itself into a symbol of rock-solid investment strategy, has revealed a stake in the big biotech as it takes on one of the biggest gambles in the industry.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 72,400+ biopharma pros reading Endpoints daily — and it's free.