Fatty liver conceptual image, 3D illustration showing fatty liver silhouette made from micrograph of liver steatosis (Shutterstock)

The path to NASH: un­der­stand­ing the role of se­vere obe­si­ty in a com­plex, mul­ti-sys­tem dis­ease

Biotech Voices is a collection of exclusive opinion editorials from some of the leading voices in biopharma on the biggest industry questions today. Think you have a voice that should be heard? Reach out to senior editors Kyle Blankenship and Amber Tong.

We of­ten think a per­son’s tran­si­tion from a healthy to a dis­eased state is bi­na­ry. But that’s of­ten not the case. In re­al­i­ty, the on­set of a dis­ease is not some­thing that oc­curs overnight, and the ma­jor­i­ty lie on a con­tin­u­um that is im­pact­ed by a mul­ti­tude of fac­tors. Some of these fac­tors are in a pa­tient’s con­trol. Oth­ers are not.

This is the case in non­al­co­holic fat­ty liv­er dis­ease (NAFLD) and non­al­co­holic steato­hep­ati­tis (NASH), two of the most com­plex dis­eases that “live” on this prover­bial con­tin­u­um. The clin­i­cal on­set of NAFLD — and ul­ti­mate­ly NASH — is a com­plex process that is close­ly re­lat­ed to obe­si­ty, in­sulin re­sis­tance and im­paired adi­pose tis­sue me­tab­o­lism.

For ex­am­ple, the preva­lence of NAFLD cor­re­lates with the in­creas­ing preva­lence of obe­si­ty. Sim­i­lar re­search has emerged in the NASH space: In a study an­a­lyz­ing pa­tients who sub­mit­ted to bariatric surgery, 70.4% of those pa­tients had NASH. The da­ta sug­gest that the world­wide preva­lence of obe­si­ty among NAFLD and NASH pa­tients is 51% and 81%, re­spec­tive­ly, and in pop­u­la­tions with obe­si­ty, NAFLD preva­lence varies from 60% to 95%.

While it is clear that a ma­jor con­trib­u­tor on this NASH con­tin­u­um is se­vere obe­si­ty, it pos­es its own set of chal­lenges. NASH re­searchers and drug de­vel­op­ers of­ten strug­gle to com­mu­ni­cate the role obe­si­ty plays in dis­ease on­set and pro­gres­sion in a way that is both kind and em­pa­thet­ic — and al­so sci­en­tif­i­cal­ly ac­cu­rate. That be­ing said, how­ev­er dif­fi­cult it is to achieve this del­i­cate bal­ance, it is cru­cial in or­der to ap­proach treat­ment holis­ti­cal­ly.

This is the chal­lenge we face as a com­pa­ny work­ing to ther­a­peu­ti­cal­ly ad­dress a dis­ease that is (in part) a re­sult of lifestyle choic­es. There’s an as­so­ci­at­ed stig­ma that gets placed on the in­di­vid­ual, and many strug­gle with feel­ing re­spon­si­ble for de­vel­op­ing a dis­ease that is so heav­i­ly linked to obe­si­ty and a low-ac­tiv­i­ty lifestyle.

The se­vere obe­si­ty that plagues most peo­ple with NASH comes with mo­bil­i­ty chal­lenges, and rou­tine, day-to-day tasks of­ten prove to be ma­jor hur­dles for peo­ple with this dis­ease. This fu­els a down­ward spi­ral of anx­i­ety, self-re­crim­i­na­tion and doubt, and in­di­vid­u­als will of­ten face poor self-es­teem fa­tigue and de­pres­sion as a re­sult. As a part of the biotech and health­care com­mu­ni­ties, our goal here is to judge, help, ed­u­cate and pro­vide mean­ing­ful treat­ment op­tions to the in­di­vid­u­als who need them most.

For ex­am­ple, this in­cludes ed­u­cat­ing peo­ple of the long-term risks as­so­ci­at­ed with years of an ex­cess of calo­ries con­sumed rel­a­tive to en­er­gy con­sump­tion. While we know that obe­si­ty can lead to a va­ri­ety of dis­eases and ail­ments, the ef­fects of a chron­ic ex­cess of calo­ries are not nec­es­sar­i­ly ob­vi­ous to every­one. The re­al­i­ty is that NASH, di­a­betes, car­dio­vas­cu­lar dis­ease (and more) are all con­nect­ed to a sur­feit of calo­ries over an ex­tend­ed pe­ri­od of time, and this ex­cess ul­ti­mate­ly dri­ves dis­ease pro­gres­sion.

What we need are open, com­pas­sion­ate con­ver­sa­tions that en­able in­di­vid­u­als to ex­plore where they are on this dis­ease con­tin­u­um and how to es­tab­lish bet­ter, health­i­er lifestyle choic­es. It’s not about sit­ting in judg­ment or “fat sham­ing.” It’s about ful­ly un­der­stand­ing how obe­si­ty and oth­er fac­tors can man­i­fest in dis­ease lat­er down the road. While most dis­ease pro­gres­sion lies on a con­tin­u­um, this is par­tic­u­lar­ly true for NASH.

In­di­vid­u­als should be helped to un­der­stand that obe­si­ty can be an avoid­able — and re­versible — pre­cur­sor to the dis­ease to en­sure that they re­ceive the best care pos­si­ble. Peo­ple ei­ther at risk for or liv­ing with NASH can im­prove their over­all health if they are will­ing to take a more ac­tive role in man­ag­ing their risk fac­tors. This can in­clude re­duc­ing calo­rie in­take and in­creas­ing ac­tiv­i­ty to re­duce weight, but oth­er vari­ables with re­spect to their health must al­so be con­sid­ered. For in­stance, in­di­vid­u­als at risk for NASH are fre­quent­ly pre­scribed a pletho­ra of oth­er med­ica­tions such as high blood pres­sure med­i­cines, di­a­betes drugs or statins, and anx­i­ety and de­pres­sion treat­ments for ad­di­tion­al dis­or­ders as­so­ci­at­ed with obe­si­ty.

Chang­ing eat­ing habits can im­pact drug ac­tiv­i­ty in the body and may cause un­fore­seen com­pli­ca­tions that should be tak­en in­to con­sid­er­a­tion to en­sure op­ti­mal care. That is why we can­not shy away from these con­ver­sa­tions, even as we prac­tice em­pa­thy and com­pas­sion.

NASH is a com­plex, mul­ti-sys­tem dis­ease, re­quir­ing pa­tient care and ther­a­peu­tics that ad­dress its mul­ti-fac­to­r­i­al na­ture. But treat­ing NASH ex­tends be­yond its clin­i­cal pro­file – it goes back to this no­tion of the con­tin­u­um. Clin­i­cians, re­searchers and drug de­vel­op­ers must ex­am­ine the en­tire per­son, con­fronting both the phys­i­cal and emo­tion­al tolls of NASH. The on­ly way to do this is through open and hon­est con­ver­sa­tions about the role of obe­si­ty in the dis­ease. On­ly then can we be­gin to ef­fec­tive­ly help the peo­ple who face this di­ag­no­sis.

Biotech and Big Phar­ma: A blue­print for a suc­cess­ful part­ner­ship

Strategic partnerships have long been an important contributor to how drugs are discovered and developed. For decades, big pharma companies have been forming alliances with biotech innovators to increase R&D productivity, expand geographical reach and better manage late-stage commercialization costs.

Noël Brown, Managing Director and Head of Biotechnology Investment Banking, and Greg Wiederrecht, Ph.D., Managing Director in the Global Healthcare Investment Banking Group at RBC Capital Markets, are no strangers to the importance of these tie-ups. Noël has over 20 years of investment banking experience in the industry. Before moving to the banking world in 2015, Greg was the Vice President and Head of External Scientific Affairs (ESA) at Merck, where he was responsible for the scientific assessment of strategic partnership opportunities worldwide.

No­var­tis' sec­ond at­tempt to repli­cate a stun­ning can­cer re­sult falls flat

Novartis’ hopes of turning one of the most surprising trial data points of the last decade into a lung cancer drug has taken another setback.

The Swiss pharma announced Monday that its IL-1 inhibitor canakinumab did not significantly extend the lives or slow the disease progression of patients with previously untreated locally advanced or metastatic non-small cell lung cancer when compared to standard of-care alone.

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Robert Califf (Pablo Martinez Monsivais, AP Images, File)

As buzz on Califf FDA nom heats up, in­dus­try and agency in­sid­ers of­fer a strong nod for the ‘per­fect’ choice

For once in this long, dramatic road to finding a new FDA commissioner, there’s been some continuity. Both CNN and Politico reported this weekend that Rob Califf met with President Biden to discuss the permanent commish role, following earlier news broken by the Washington Post that all signs point to Califf.

Although there may be a few Democrats who continue to grandstand about the dangers of COI (Califf has worked for Verily, sits on the board of Centessa Pharmaceuticals, and has other ties to industry research), with the pandemic ongoing and the need for some kind of continuity at FDA mounting, Califf is likely to meet the same fate as when he first won Senate confirmation in 2016, by a vote of 89-4 — Bernie Sanders and 6 others didn’t vote.

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AstraZeneca CEO Pascal Soriot (Raphael Lafargue/Abaca/Sipa USA)

A com­bo of As­traZeneca's Imfinzi and chemo wins where oth­ers have failed in piv­otal bil­iary tract test

Looking to run with the big dogs in the PD-(L)1 class, AstraZeneca’s Imfinzi has a tall hill to climb to compete in an increasingly bustling market. An aggressive combo strategy for the drug has paid off so far, and now AstraZeneca is adding another notch to its belt.

A combo of Imfinzi (durvalumab) and chemotherapy significantly extended the lives of first-line patients with advanced biliary tract cancer over chemo alone, according to topline results from the Phase III TOPAZ-1 study revealed Monday.

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Sean Ianchulev, Eyenovia CEO and CMO

Re­cent court de­ci­sion push­es FDA to re­ject and re­clas­si­fy drug-de­vice com­bo, crush­ing shares

Back in April, the FDA lost a crucial court case in which its broad discretion of regulating medical products that might satisfy the legal definitions of either “drug” and/or “medical device” was sharply curtailed.

In addition to the appeals court ruling that Genus Medical Technologies’ contrast agent barium sulfate (aka Vanilla SilQ) should not be considered a drug, as the FDA had initially ruled, but as a medical device, the agency also was forced to spell out which drugs would transition to devices as a result of the ruling.

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Peter Greenleaf, Aurinia CEO

Af­ter pass­ing on Ac­celeron, Bris­tol My­ers eyes bolt-on ac­qui­si­tion of au­toim­mune spe­cial­ist — re­port

Bristol Myers Squibb is looking to beef up its autoimmune portfolio by scooping up Aurinia Pharmaceuticals, Bloomberg reported.

The recent overtures to Aurinia, relayed by anonymous insiders, came just as Bristol Myers turned down buyout talks with partners at Acceleron — which Merck ultimately struck a deal to acquire for $11.5 billion. Bristol Myers has reportedly decided to cash out on its minority stake, likely bagging $1.3 billion in the process, while keeping the royalty deals on two of Acceleron’s blood disorder drugs.

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So — that pig-to-hu­man trans­plant; Po­ten­tial di­a­betes cure reach­es pa­tient; Ac­cused MIT sci­en­tist lash­es back; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

We’re incredibly excited to welcome Beth Bulik, seasoned pharma marketing reporter, to the team. You can find much of her work in our new Marketing channel — and in her weekly newsletter, Endpoints PharmaRx, which will launch in early November. Add it to your subscriptions here.

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NYU surgeon transplants an engineered pig kidney into the outside of a brain-dead patient (Joe Carrotta/NYU Langone Health)

No, sci­en­tists are not any clos­er to pig-to-hu­man trans­plants than they were last week

Steve Holtzman was awoken by a 1 a.m. call from a doctor at Duke University asking if he could put some pigs on a plane and fly them from Ohio to North Carolina that day. A motorcyclist had gotten into a horrific crash, the doctor explained. He believed the pigs’ livers, sutured onto the patient’s skin like an external filter, might be able to tide the young man over until a donor liver became available.

UP­DAT­ED: Agenus calls out FDA for play­ing fa­vorites with Mer­ck, pulls cer­vi­cal can­cer BLA at agen­cy's re­quest

While criticizing the FDA for what may be some favoritism towards Merck, Agenus on Friday officially pulled its accelerated BLA for its anti-PD-1 inhibitor balstilimab as a potential second-line treatment for cervical cancer because of the recent full approval for Merck’s Keytruda in the same indication.

The company said the BLA, which was due for an FDA decision by Dec. 16, was withdrawn “when the window for accelerated approval of balstilimab closed,” thanks to the conversion of Keytruda’s accelerated approval to a full approval four months prior to its PDUFA date.

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