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.

No­var­tis reshuf­fles its wild cards; Tough sell for Bio­gen? Googling pro­teins; Ken Fra­zier's new gig; 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.

If you enjoy the People section in this report, you may also want to check out Peer Review, my colleagues Alex Hoffman and Kathy Wong’s comprehensive compilation of comings and goings in biopharma.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 112,600+ biopharma pros reading Endpoints daily — and it's free.

Demis Hassabis, DeepMind CEO (Qianlong/Imaginechina via AP Images)

Google's Deep­Mind opens its pro­tein data­base to sci­ence — po­ten­tial­ly crack­ing drug R&D wide open

Nearly a year ago, Google’s AI outfit DeepMind announced they had cracked one of the oldest problems in biology: predicting a protein’s structure from its sequence alone. Now they’ve turned that software on nearly every human protein and hundreds of thousands of additional proteins from organisms important to medical research, such as fruit flies, mice and malaria parasite.

The new database of roughly 350,000 protein sequences and structures represents a potentially monumental achievement for the life sciences, one that could hasten new biological insights and the development of new drugs. DeepMind said it will be free and accessible to all researchers and companies.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 112,600+ biopharma pros reading Endpoints daily — and it's free.

In­side Bio­gen's scram­ble to sell Aduhelm: Pro­ject 'Javelin' and pres­sure to ID as many pa­tients as pos­si­ble

In anticipation of Aduhelm’s approval for Alzheimer’s in June, Biogen employees were directed to identify and guarantee treatment centers would administer the drug through a program called “Javelin,” a senior Biogen employee told Endpoints News.

The program identified about 800 centers for use, he said, and Biogen now pays for the use of bioassays to identify beta amyloid in potential patients having undergone a lumbar puncture procedure, the employee said — and one center preparing to administer the drug confirmed its participation in the bioassay program.

Endpoints Premium

Premium subscription required

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

Vas Narasimhan, Novartis CEO (Jason Alden/Bloomberg via Getty Images)

No­var­tis dis­cards one of its ‘wild card’ drugs af­ter it flops in key study. But it takes one more for the hand

Always remember just how risky it is to gamble big on small studies.

A little more than 4 years ago, Novartis reportedly put up a package worth up to $1 billion for the dry eye drug ECF843 after a small biotech called Lubris put it through its paces in a tiny study of 40 moderate to severe patients, tracking some statistically significant markers of efficacy.

By last fall, the program had risen up to become one of CEO Vas Narasimhan’s top “wild card” programs in line for a potential breakthrough year in 2021. These drugs were all considered high-risk, high-reward efforts. And in this case, risk won.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 112,600+ biopharma pros reading Endpoints daily — and it's free.

EMA re­jects FDA-ap­proved Parkin­son's drug, signs off on Mod­er­na vac­cine use in ado­les­cents ahead of FDA

The European Medicines Agency on Friday rejected Kyowa Kirin’s Parkinson’s disease drug Nouryant (istradefylline), which the US FDA approved in 2019 under the brand name Nourianz.

EMA said it considered that the results of the clinical studies used to support the application “were inconsistent and did not satisfactorily show that Nouryant was effective at reducing the ‘off’ time. Only four out of the eight studies showed a reduction in ‘off’ time, and the effect did not increase with an increased dose of Nouryant.”

6 top drug­mak­ers of­fer per­spec­tives on FDA's new co­vari­ates in RCTs guid­ance

Back in May, the FDA revised and expanded a 2019 draft guidance that spells out how to adjust for covariates in the statistical analysis of randomized controlled trials.

Building on the ICH’s E9 guideline on the statistical principles for clinical trials, the 3-page draft was transformed into an 8-page draft, with more detailed recommendations on linear and nonlinear models to analyze the efficacy endpoints in RCTs.

Endpoints Premium

Premium subscription required

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

Mol­e­c­u­lar Di­ag­nos­tics Can Trans­form Can­cer Care. Let’s Make It Hap­pen.

Like so many people around the world, my life has been profoundly shaped by cancer. Those personal experiences, along with a deep love of clinical laboratory science and a passion to apply the power of genomics in medicine, motivated me to launch a company that would improve cancer care through better diagnostics. Thirteen years later, I am proud that we are delivering more accurate information at multiple points along the patient journey, with a focus on eight of the 10 cancers that are most commonly diagnosed in the United States.

Mod­er­na es­tab­lish­es pub­lic health-fo­cused char­i­ty; FDA ap­proves As­traZeneca di­a­betes drug for pe­di­atric use

To help promote public health and healthcare in underserved areas of the world, Moderna will establish a charity with a $50 million endowment.

The Cambridge, MA-based company announced the board of directors’ approval Thursday. The foundation will focus on “charitable, scientific and educational endeavors” with an emphasis on promoting public health and the access to healthcare, the press release said. The foundation will start operations once its status as a 501(c)(3) is approved.

UP­DAT­ED: Three biotechs price hefty IPOs just be­fore the week­end, while a fourth and a SPAC seek spots on Wall Street

Editor’s note: Interested in following biopharma’s fast-paced IPO market? You can bookmark our IPO Tracker here.

A handful of biotechs are hitting Wall Street just before the start of the weekend, with three companies — Caribou Biosciences, Sophia Genetics and Absci — all pricing big raises Wednesday and Thursday. Gamma delta T cell-focused IN8bio relaunched its IPO campaign months after postponing it last November, seeking a slightly lower raise. And another SPAC has filed for a public debut.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 112,600+ biopharma pros reading Endpoints daily — and it's free.