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 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.

Op­ti­miz­ing Cell and Gene Ther­a­py De­vel­op­ment and Pro­duc­tion: How Tech­nol­o­gy Providers Like Corn­ing Life Sci­ences are Spurring In­no­va­tion

Remarkable advances in cell and gene therapy over the last decade offer unprecedented therapeutic promise and bring new hope for many patients facing diseases once thought incurable. However, for cell and gene therapies to reach their full potential, researchers, manufacturers, life science companies, and academics will need to work together to solve the significant challenges facing the industry.

David Baker working with a student on their protein design (Jason Mast)

Sci­en­tists are fi­nal­ly learn­ing how to de­sign pro­teins from scratch. Drug de­vel­op­ment may nev­er be the same

SEATTLE — It’s a cloudy Thursday afternoon in mid-July and David Baker is reclining into the futon in his corner office at the University of Washington, arms splayed out like a daytime talk show host as he coaches another one of his postdocs through the slings and arrows of scientific celebrity.

“Be jealous of your time,” he says, before plotting ways of sneaking her out of Zooms. “It’s this horrible cost to science that you’re tied up in some stupid meeting.”

Endpoints Premium

Premium subscription required

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

Pre­sent­ing a live End­points News event: Man­ag­ing a biotech in tur­bu­lent times

Biotech is one of the smartest, best educated industries on the planet. PhDs abound. We’ve had a long enough track record to see a new generation of savvy, experienced execs coming together to run startups.

And in these times, they are being tested as never before.

Biotech is going through quite a rough patch right now. For 2 years, practically anyone with a decent resume and some half-baked ideas on biotech could start a company and get it funded. The pandemic made it easy in many ways to pull off an IPO, with traditional road shows shut down in exchange for a series of quick Zoom meetings. Generalist investors flocked as the numbers raised soared into the stratosphere.

Patty Murray, D-WA (Graeme Sloan/Sipa USA)(Sipa via AP Images)

Sen­ate user fee reau­tho­riza­tion bill omits ac­cel­er­at­ed ap­proval re­forms, shows wide gaps with House ver­sion

The Senate health committee on Tuesday released its first version of the bill to reauthorize all the different FDA user fees. But unlike the House version, there are only a few controversial items in the Senate’s version, which does not address either accelerated approval reforms or clinical trial diversity (as the House did).

While it’s still relatively early in the process of finalizing this legislation (the ultimate statutory deadline is the end of September), the House and Senate, at least initially, appear to be starting off in different corners on what should be included.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 142,200+ biopharma pros reading Endpoints daily — and it's free.

Warren Buffett, Berkshire Hathaway CEO

Berk­shire Hath­away pulls out of Ab­b­Vie, Bris­tol My­ers Squibb in­vest­ments

It looks like Warren Buffett is sticking to ice cream and railroads for the moment.

The billionaire CEO of Berkshire Hathaway backed out of two major holdings in the pharma industry, Forexlive first reported, including a $410 million investment in AbbVie and a $324.4 million stake in Bristol Myers Squibb.

The move comes after Berkshire abandoned its Teva shares just last quarter, Bloomberg reported.

Long-ex­pect­ed UK lay­offs im­mi­nent for No­var­tis fol­low­ing sale

Nearly a year ago, more than 200 workers at Novartis’ Grimsby, UK, facility were able to hang on to their jobs after the pharma closed a Switzerland site as a part of its workforce restructuring plan. Now, it looks like those employees’ time is up, as the site has been sold, Grimsby Telegraph reported today.

The manufacturing site has been sold to Humber Industrials, a subsidiary of International Process Plants. None of the current staff members will be working with the new owners, however.

Clay Siegall (Photo by Dimitrios Kambouris/Getty Images for Gabrielle's Angel Foundation)

UP­DAT­ED: Clay Sie­gall re­signs from Seagen amid in­ves­ti­ga­tion in­to do­mes­tic vi­o­lence claims

A week after Seagen revealed that longtime CEO Clay Siegall was on leave due to an allegation of domestic violence, he has resigned.

Since that shocking revelation, more details about the claims have emerged into the public eye. As Endpoints News reported, Siegall was arrested on April 23. A police report about that night and a subsequent temporary restraining order described a pattern of abusive behavior against his wife and a physical altercation that left her with multiple bruises. Siegall denied the claims.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 142,200+ biopharma pros reading Endpoints daily — and it's free.

FDA lob­bies Con­gress over rare dis­ease court rul­ing with wide im­pli­ca­tions

Usually reserved for making decisions on drug applications or enforcing what Congress stipulates, the FDA is now dipping its toe into the wild world of congressional politics as it attempts to fix a major court decision that could have a chilling effect on rare disease R&D.

The case in question from last October saw a US appeals court overturn a prior FDA court win, saying that the agency never should’ve approved a rare disease drug because a previously approved but more expensive drug with the same active ingredient has orphan drug exclusivity barring such an approval.

Peter Marks (Greg Nash/Pool via AP)

Even FDA's Pe­ter Marks is wor­ried about the com­mer­cial vi­a­bil­i­ty of gene and cell ther­a­pies

When bluebird bio’s gene therapy to treat beta thalassemia won European approval in 2019, the nearly $2 million per patient price tag for the potential cure seemed like a surmountable hurdle.

Fast forward two years later, and bluebird has withdrawn Zynteglo, the beta thal drug, along with the rest of its gene therapy portfolio from Europe, which the company said is generally unwilling to pay a fair price for the treatment.