Gilead shores up hope for NASH cock­tail with a glimpse at pos­i­tive proof-of-con­cept da­ta

When Gilead con­ced­ed fail­ure in its high-pro­file Phase III study for top late-stage NASH drug selon­sert­ib, CSO John McHutchi­son point­ed dis­ap­point­ed in­vestors to a com­bi­na­tion ap­proach be­ing test­ed in a mid-stage tri­al. Those da­ta are not ready just yet, but to­day the big biotech un­veiled some ear­ly num­bers to bol­ster their case for a cock­tail.

John McHutchi­son

On dis­play to­day at the In­ter­na­tion­al Liv­er Con­gress are topline re­sults from a proof-of-con­cept study test­ing cilofex­or (non­s­teroidal far­ne­soid X re­cep­tor or FXR ag­o­nist) and fir­so­co­stat (acetyl-CoA car­boxy­lase or ACC in­hibitor). Out of 20 pa­tients who were treat­ed with the oral reg­i­men once dai­ly for 12 weeks, 74% ex­pe­ri­enced “a sig­nif­i­cant de­cline of at least 30 per­cent in he­pat­ic fat” — a hall­mark of the dis­ease.

Re­searchers al­so doc­u­ment­ed im­prove­ments in oth­er bio­mark­ers, in­clud­ing “serum ALT (me­di­an rel­a­tive re­duc­tion, -37%; p<0.001) and GGT (-32%; p<0.001), along with mark­ers of re­duced bile acid syn­the­sis.”

Cilofex­or and fir­so­co­stat are al­so part of a triplet com­bo with the ASK1 in­hibitor selon­sert­ib, at the cen­ter of the Phase II AT­LAS study that McHutchi­son high­light­ed. In gen­er­al, FXR ac­ti­va­tion is thought to fight liv­er fi­bro­sis, ACC in­hibitors block fat­ty acid syn­the­sis, while ASK1 in­hibitor al­so helps re­duce in­flam­ma­tion.

“NASH is a com­plex dis­ease with mul­ti­ple bi­o­log­i­cal path­ways that in­flu­ence its pro­gres­sion. Com­bi­na­tion ther­a­peu­tic ap­proach­es which tar­get these path­ways, are like­ly to be need­ed to ef­fec­tive­ly treat pa­tients liv­ing with NASH, par­tic­u­lar­ly those with ad­vanced fi­bro­sis who have the great­est un­met need,” said McHutchi­son in a state­ment.

Gilead took a hit when selon­sert­ib flopped in its close­ly-watched STEL­LAR-4, out­per­formed by the place­bo at the low dose, though an­a­lysts ac­knowl­edged that fi­bro­sis was a tough tar­get to tack­le.

With a flock of small­er play­ers — in­clud­ing In­ter­cept, Gen­fit, Madri­gal and NGM Bio, which is part­nered with Mer­ck — con­tend­ing for the still va­cant NASH throne, Gilead has been pick­ing up ear­ly-stage as­sets in pur­suit of a sus­tain­ing fran­chise. In fact, cilofex­or came from the buy­out of Phenex Phar­ma and you might re­mem­ber fir­so­co­stat as GS-0976, which Gilead paid Nim­bus $600 mil­lion for.

It won’t be easy. But the pull is strong: NASH, which is typ­i­cal­ly as­so­ci­at­ed with obe­si­ty and di­a­betes, is set to eclipse he­pati­tis C as the lead­ing rea­son for liv­er trans­plants by 2020.

At the con­fer­ence, Gilead al­so pre­sent­ed screen­ing da­ta in sup­port of non-in­va­sive tests to iden­ti­fy NASH pa­tients with ad­vanced fi­bro­sis. Re­duc­ing the need for the cost­ly and risky liv­er biop­sies typ­i­cal­ly need­ed for the di­ag­no­sis can pave a smoother path for pa­tients to­ward treat­ment — ul­ti­mate­ly when they get ap­proved.


Im­age: Shut­ter­stock

Jean-Paul Clozel, Idorsia CEO (Patrick Straub/Keystone via AP Images)

Idor­si­a's brain bleed drug flunks PhI­II tri­al, a decade af­ter pre­vi­ous flop

Idorsia’s long journey with clazosentan came to an abrupt “unexpected result” Monday morning with a Phase III flop.

The Swiss biopharma said the drug did not meet the main goal of the late-stage REACT study, conducted in the US, Canada and Europe since early 2019.

The 409-patient trial tested the intravenous drug’s ability to prevent complications due to delayed cerebral ischemia following aneurysmal subarachnoid hemorrhage (aSAH), in which blood vessels in the brain narrow and blood accumulates around the brain’s surface, which then dials up the pressure on the brain.

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Kenji Yasukawa, Astellas Pharma CEO (Photographer: Akio Kon/Bloomberg via Getty Images)

Astel­las taps chief strat­e­gy of­fi­cer as next CEO to 'go on the ag­gres­sive'

Five years into its big R&D revamp, Astellas says it’s time for a changing of the guard.

Kenji Yasukawa, who took over as president and CEO in 2018, will step down to become chairman of the board in April, making room for Naoki Okamura to take over. Okamura joined the company in 1986 and has served in a variety of finance, business and strategy roles, including most recently as chief strategy officer.

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Clin­i­cal tri­al di­ver­si­ty da­ta show mis­match be­tween en­roll­ment and dis­ease preva­lence, GSK says

A lack of diversity in clinical trials has persisted despite decades of initiatives to try to turn the tide.

In a recent review of 17 years of clinical trials, drugmaker GSK found that there were some mismatches between the demographics of its US-based trials and how prevalent diseases were in those populations.

The results, the company says, will help GSK and others design studies that better represent epidemiological rates within races and ethnicities.

The Big Phar­ma dis­card pile; Lay­offs all around while some biotechs bid farewell; New Roche CEO as­sem­bles top team; 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.

With earnings seasons in full swing, we’ve listened in on all the calls so you don’t have to. But news is popping up from all corners, so make sure you check out our other updates, too.

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Ma­gen­ta halts stem cell work and may sell it­self fol­low­ing pa­tient death, clin­i­cal hold

Magenta Therapeutics said it is halting work on its stem cell transplant drug pipeline and may sell itself, a week after the company reported the death of a patient in an early stage trial of its antibody-drug conjugate.

The Cambridge, MA-based company said it will conduct a “review of strategic alternatives,” and that could include an “acquisition, merger, business combination, or other transaction.”

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How to use ex­ter­nal con­trols: FDA spells out think­ing in new draft guid­ance

The use of real-world evidence to inform the FDA’s decision-making continues apace, with the agency releasing new draft guidance yesterday on how sponsors can compare outcomes of trial participants receiving a test treatment with outcomes in a group of people external to the trial.

The practice of externally controlled trials is common, particularly in oncology or other difficult areas where it’s not ethical or feasible to use internal controls.

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The Big Phar­ma axe: Mer­ck cuts chikun­gun­ya vax, Bris­tol My­ers drops Cy­tomX-part­nered pro­gram, and more

As fourth quarter earnings come in, Big Pharmas are disclosing changes to their pipelines during their investor calls, and sometimes more quietly in presentation appendices.

Merck dropped its chikungunya vaccine candidate, which completed a Phase II study. Merck acquired the vaccine through its purchase of Themis Bioscience in 2020. In developing a vaccine for chikungunya, a mosquito-borne virus, Valneva is the frontrunner, as it submitted its vaccine to the FDA at the end of December.

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Goldfinch Bio CEO Tony Johnson (L) and Karuna Therapeutics CEO Bill Meury

Karuna li­cens­es Goldfinch as­sets to com­pete with Boehringer In­gel­heim in neu­ro­science

Karuna Therapeutics is looking to compete with Boehringer Ingelheim on depression and anxiety with a new license to Goldfinch Bio’s assets, starting with $15 million to the shuttered biotech.

Karuna steps into an arena already being tested by Boehringer in multiple Phase II studies — the two are targeting transient receptor potential canonical 4 and 5, or TRPC4/5, which is thought to have a role in neuroscience indications. Goldfinch’s asset went through a Phase II in kidney diseases, but Karuna’s sights are set on mood and anxiety disorders for now.

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Roche's headquarters in Basel, Switzerland (Kyle LaHucik for Endpoints News)

Roche ditch­es fi­nal PhI­II for can­cer hope­ful, re­ports set­back for key drug in $1.4B buy­out

Over the past few years, Roche has released news about its AKT inhibitor ipatasertib in drips — most of them negative. The drug yielded mixed data in a key prostate cancer trial, Phase III flops in triple-negative breast cancer forced the pharma giant to pull the plug there, and in mid-2022 Roche trimmed two more early-stage indications in prostate cancer after completing the trials.

Now, the last piece of the program is gone.

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