Terns Phar­ma­ceu­ti­cals touts safe­ty da­ta from an ex-Eli Lil­ly can­di­date in the hunt for NASH treat­ment

While many oth­ers have tried — and failed — to get a NASH can­di­date across the fin­ish line, Terns Phar­ma­ceu­ti­cals thinks its FXR ag­o­nist will even­tu­al­ly earn its wings with­out the safe­ty is­sues that have slowed oth­ers down. Now, a mid-stage safe­ty read­out could help add some va­lid­i­ty to those hopes.

No pa­tients in the Phase IIa LIFT study dis­con­tin­ued TERN-101 due to side ef­fects, CMO Erin Quirk said dur­ing a call with in­vestors on Mon­day morn­ing. That in­cludes pru­ri­tus, an un­com­fort­able itch­ing sen­sa­tion that fre­quent­ly leads pa­tients to drop out of oth­er FXR ag­o­nist stud­ies.

Senthil Sun­daram

“This is the first of sev­er­al im­por­tant mile­stones that pro­vide val­i­da­tion for Terns’ pipeline over the next 12 months or so,” CEO Senthil Sun­daram said.

NASH, or non­al­co­holic steato­hep­ati­tis, refers to fat buildup in the liv­er that caus­es in­flam­ma­tion and scar­ring. TERN-101 tar­gets FXR, a nu­clear re­cep­tor in the liv­er, in­tes­tine and kid­neys that reg­u­lates the he­pat­ic ex­pres­sion of var­i­ous genes in­volved in lipid me­tab­o­lism, in­flam­ma­tion and fi­bro­sis.

Eleven out of the 74 pa­tients treat­ed with TERN-101 came down with pru­ri­tus, in­clud­ing four in the high­est dose group, Terns said. Pa­tients re­ceived one of three dos­es — 5 mg, 10 mg or 15 mg — over 12 weeks. There were no treat­ment-re­lat­ed se­ri­ous ad­verse events, as two cas­es of Covid-19 and a UTI that sent pa­tients to the hos­pi­tal were not linked to the can­di­date.

“TERN-101 is more high­ly liv­er-dis­trib­uted than oth­er FXR ag­o­nists that have been stud­ied in NASH pa­tients,” Quirk said dur­ing the call, adding that da­ta sug­gest the can­di­date pri­mar­i­ly ac­ti­vates FXR in the liv­er, rather than the in­tes­tine or oth­er or­gans. “We be­lieve that TERN-101’s dif­fer­en­ti­at­ed safe­ty and tol­er­a­bil­i­ty pro­file and im­proved tar­get en­gage­ment, rel­a­tive to oth­er FXR ag­o­nists, is be­cause of its ac­tiv­i­ty in the liv­er.”

Oth­er NASH can­di­dates have run in­to trou­ble with raised LDL cho­les­terol, which in turn can raise car­dio­vas­cu­lar risk. No change in LDL cho­les­terol was re­port­ed in the first two dose groups, but a sta­tis­ti­cal­ly sig­nif­i­cant change (15.9%) was seen in the 15 mg group.

Re­searchers al­so not­ed im­prove­ments in a bio­mark­er known as cor­rect­ed T1 (cT1) re­lax­ation time, an MRI-based test mea­sur­ing free-wa­ter con­tent in liv­er tis­sue. Im­prove­ments of at least 80 mil­lisec­onds were seen in a sig­nif­i­cant pro­por­tion of pa­tients in the 5 mg and 10 mg groups at Week 12 com­pared to place­bo, and sig­nif­i­cant de­creas­es in cT1 were re­port­ed at Week 6 for all dose groups, ac­cord­ing to Terns.

Erin Quirk

“LIFT is the first con­trolled NASH tri­al to show sig­nif­i­cant cT1 im­prove­ment as ear­ly as Week 6,” Quirk said.

Mean rel­a­tive changes in MRI pro­ton den­si­ty fat frac­tion (MRI-PDFF), an imag­ing mark­er that mea­sures liv­er fat con­tent, were -8.4% in the place­bo arm, -15.1% in the 5 mg arm, -19.7% in the 10 mg arm, and -12.9% in the 15 mg arm at Week 12. While the rel­a­tive changes were sig­nif­i­cant at Week 6 for the 10 and 15 mg groups com­pared to place­bo, they weren’t sta­tis­ti­cal­ly sig­nif­i­cant at Week 12, Terns said.

Mean changes in ala­nine transam­i­nase lev­els (ALT), which can in­di­cate a liv­er prob­lem, were -5.3% (place­bo), -2.6% (5 mg), -18% (10 mg), and -13.2% (15 mg).

Terns $TERN stock was up 9% up­on shar­ing the news ear­ly Mon­day morn­ing, then slipped 4% about an hour lat­er.

Terns bagged the rights to TERN-101 back in 2018, along with two oth­er NASH can­di­dates from Eli Lil­ly. Its TERN501, a thy­roid hor­mone re­cep­tor be­ta ag­o­nist, is cur­rent­ly in Phase I, and a com­bi­na­tion tri­al of the two is ex­pect­ed to kick off in the first half of next year.

While 2019 was ini­tial­ly dubbed “The Year of NASH” by Gold­man Sachs, the year quick­ly turned in­to the year of NASH fail­ures, the most no­table among them Gilead’s. CymaBay went from a $1 bil­lion com­pa­ny to a $100 mil­lion com­pa­ny af­ter they found their drug ap­peared to be mak­ing pa­tients worse. Cir­ius with­drew an $86 mil­lion IPO bid af­ter a bad read­out.

The bad luck con­tin­ued in­to 2020, as In­ter­cept, which pulled ahead with pos­i­tive Phase III re­sults, wound up with a re­jec­tion for their long-watched NASH drug last June. And af­ter fail­ing a Phase III show­down, Gen­fit ex­it­ed NASH al­to­geth­er and made plans to lay off 40% of its work­force back in Oc­to­ber.

Ab­b­Vie cur­rent­ly has a Phase I FXR ag­o­nist for NASH, which it in­her­it­ed in the Al­ler­gan buy­out.

At first, the idea be­hind Terns — named af­ter the small, tough wa­ter bird — was to part­ner a Cal­i­for­nia-based dis­cov­ery team with a small de­vel­op­ment group in Chi­na to ef­fi­cient­ly de­vel­op new drugs pri­mar­i­ly for the Chi­nese mar­ket. But back in Jan­u­ary, a spokesper­son for the com­pa­ny told End­points News that the com­pa­ny has since shift­ed to fo­cus more on build­ing a head­quar­ters and de­vel­op­ment team in Cal­i­for­nia.

While Terns con­tin­ues to “have an eye on ad­di­tion­al glob­al mar­kets,” their cur­rent fo­cus is on the US, where clin­i­cal tri­als for their three lead pro­grams will oc­cur, the spokesper­son said.

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.

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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.

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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.

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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.

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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.

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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.”

Laurent Fischer, Adverum CEO

Ad­verum faces murky fu­ture af­ter re­view turns up deep­er safe­ty is­sues for gene ther­a­py

Three months after revealing that a patient lost significant vision in one eye after receiving its experimental gene therapy, Adverum announced it found the safety issues were more widespread: Five of 12 patients who received a high dose of the therapy saw “similar clinically-relevant events.”

Three required surgery on their treated eye. And all 12 are being recommended “aggressive immunomodulatory treatments” to prevent further injury.

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Al Sandrock, Biogen R&D chief (Biogen via YouTube)

Bio­gen has a shaky end to H1 with a $542M write-off adding to its woes — but an­a­lysts see big rev­enue ahead for Aduhelm

All eyes at Biogen’s Q2 earnings call Thursday were on Aduhelm, but investors also got a glimpse of what Biogen would have faced had the FDA not opted to approve their controversial Alzheimer’s drug.

That glimpse, revealing a combination of declining sales, growing competition and failed medicines, underscores the stakes of the big biotech’s Aduhelm efforts, as execs punch back at the criticism they’ve engendered in the political and medical world and vigorously pushes its sales staff to roll out the drug as fast as possible.

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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.