Lit­tle Cona­tus' No­var­tis-part­nered liv­er drug suf­fers third straight de­feat, but CEO Men­to is still hold­ing out hope

Lit­tle Cona­tus’ No­var­tis-part­nered liv­er drug is one step clos­er to the scrap heap, with its third mid-stage fail­ure.

The Swiss drug­mak­er hand­ed the San Diego-based biotech $50 mil­lion up­front and an in­jec­tion of con­fi­dence in late 2016 to li­cense the drug, em­ri­c­as­an. Since then, it has flopped in a tri­fec­ta of stud­ies. An­oth­er Phase II study is ex­pect­ed to read­out lat­er this year.

Steven Men­to

The 318-pa­tient tri­al, dubbed EN­CORE-NF, was test­ing two dos­es (5 mg, 50 mg) of the drug against a place­bo in biop­sy-con­firmed NASH and liv­er fi­bro­sis pa­tients. Em­ri­c­as­an missed the pri­ma­ry end­point of im­prov­ing fi­bro­sis by ≥1 on the val­i­dat­ed Clin­i­cal Re­search Net­work (CRN) stage sys­tem, with no wors­en­ing of steato­hep­ati­tis com­pared to place­bo at week 72, the com­pa­ny said late Thurs­day.

In a sep­a­rate fil­ing, Cona­tus pro­vid­ed a lit­tle more tri­al de­tail. The re­sponse rates in the 5 mg em­ri­c­as­an, 50 mg em­ri­c­as­an and place­bo treat­ment groups were 11.2%, 12.3% and 19.0%, re­spec­tive­ly. Sta­tis­ti­cal­ly sig­nif­i­cant re­duc­tions were ob­served in ALT (el­e­vat­ed lev­els of this en­zyme in­di­cates a liv­er in dis­tress) and Cas­pase 3/7 (en­zymes that play es­sen­tial roles in pro­grammed cell death) in the 5 mg and 50 mg em­ri­c­as­an treat­ment groups.

The com­pa­ny’s shares $CNAT more than halved pre-mar­ket on Fri­day to $1.43.

Akin to the pre­vi­ous fail­ures, Cona­tus’ CEO played it cool, sug­gest­ing the drug could still work in pa­tients with NASH, which is typ­i­cal­ly as­so­ci­at­ed with obe­si­ty and di­a­betes and is set to eclipse he­pati­tis C as the lead­ing rea­son for liv­er trans­plants by 2020.

“Al­though em­ri­c­as­an did not have the de­sired ef­fect in these ear­li­er-stage NASH fi­bro­sis pa­tients, we be­lieve its demon­strat­ed bio­mark­er ac­tiv­i­ty across a broad spec­trum of liv­er dis­ease war­rants con­tin­ued eval­u­a­tion in more ad­vanced-stage NASH cir­rho­sis pa­tients,” chief Steven Men­to said in a state­ment, adding that the com­pa­ny would await ad­di­tion­al da­ta read­outs lat­er this year be­fore de­ter­min­ing the next steps for the em­ri­c­as­an pro­gram with No­var­tis.

Stifel’s Stephen Wil­ley did not buy what Cona­tus was sell­ing. “The fail­ure…fur­ther lim­its our abil­i­ty to gen­er­ate any lin­ger­ing en­thu­si­asm for re­main­ing full year 2019 mile­stones.”

“The lim­it­ed ef­fi­ca­cy de­tails pro­vid­ed by man­age­ment ac­tu­al­ly sug­gest­ed a di­rec­tion­al detri­ment in em­ri­c­as­an-treat­ed pa­tients…the lack of any clin­i­cal con­se­quences as­so­ci­at­ed with these ben­e­fits is con­sis­tent with every oth­er em­ri­c­as­an study re­port­ed to date.”

Last April, em­ri­c­as­an failed its first Phase II tri­al, in­volv­ing liv­er trans­plant pa­tients with fi­bro­sis or cir­rho­sis. In De­cem­ber, the drug failed to im­press in a sec­ond study (dubbed EN­CORE-PH), in­volv­ing NASH cir­rho­sis pa­tients — whose liv­ers were cop­ing with the dam­age and still able to per­form im­por­tant func­tions, but were at high risk for de­com­pen­sa­tion.

Wil­ley pre­dict­ed the Phase IIb EN­CORE-LF tri­al, slat­ed for read­out in mid-2019 and in­volv­ing de­com­pen­sat­ed NASH pa­tients, is al­so doomed to fail, giv­en that the 5/25mg em­ri­c­as­an dos­es giv­en in EN­CORE-PH ac­tu­al­ly re­sult­ed in wors­en­ing of symp­toms in pa­tients with base­line de­com­pen­sat­ed cir­rho­sis.

“(T)he on­ly em­ri­c­as­an dose with­in EN­CORE-PH to sug­gest an in­cre­men­tal ben­e­fit in de­com­pen­sat­ed pa­tients was the 50mg dose – which isn’t even be­ing eval­u­at­ed in EN­CORE-LF. We al­so be­lieve EN­CORE-LF-el­i­gi­ble pa­tients rep­re­sent a very dif­fi­cult-to-treat pop­u­la­tion of pa­tients in whom the na­ture and rate of events are of­ten both dif­fi­cult to pre­dict and un­cor­re­lat­ed to sup­port­ive care ther­a­py – mak­ing the achieve­ment of a sta­tis­ti­cal win in this set­ting an even more-chal­leng­ing en­deav­or.”

NASH — char­ac­ter­ized by a buildup of ex­cess fat in the liv­er that in­duces chron­ic in­flam­ma­tion and even­tu­al­ly cul­mi­nates in scar­ring that can lead to cir­rho­sis, liv­er fail­ure, can­cer and death — is a high risk-re­ward dis­ease that has at­tract­ed a pletho­ra of drug­mak­ers big and small, and re­searchers ex­pect it will take a cock­tail of new drugs to tru­ly de­feat the dis­ease.

In­ter­cept $ICPT in Feb­ru­ary re­port­ed that a piv­otal late-stage study test­ing its OCA treat­ment hit a high­ly sta­tis­ti­cal­ly sig­nif­i­cant score on an im­prove­ment in liv­er fi­bro­sis with­out any wors­en­ing of NASH, but missed the end­point for NASH res­o­lu­tion with­out wors­en­ing of fi­bro­sis. Gilead $GILD, mean­while, ex­pe­ri­enced a ma­jor set­back af­ter its NASH drug selon­sert­ib failed its Phase III. France’s Gen­fit is ex­pect­ed to of­fer its key NASH read­out lat­er this year.

Biotech Half­time Re­port: Af­ter a bumpy year, is biotech ready to re­bound?

The biotech sector has come down firmly from the highs of February as negative sentiment takes hold. The sector had a major boost of optimism from the success of the COVID-19 vaccines, making investors keenly aware of the potential of biopharma R&D engines. But from early this year, clinical trial, regulatory and access setbacks have reminded investors of the sector’s inherent risks.

RBC Capital Markets recently surveyed investors to take the temperature of the market, a mix of specialists/generalists and long-only/ long-short investment strategies. Heading into the second half of the year, investors mostly see the sector as undervalued (49%), a large change from the first half of the year when only 20% rated it as undervalued. Around 41% of investors now believe that biotech will underperform the S&P500 in the second half of 2021. Despite that view, 54% plan to maintain their position in the market and 41% still plan to increase their holdings.

David Livingston (Credit: Michael Sazel for CeMM)

Renowned Dana-Far­ber sci­en­tist, men­tor and bio­phar­ma ad­vi­sor David Liv­ingston has died

David Livingston, the Dana-Farber/Harvard Med scientist who helped shine a light on some of the key molecular drivers of breast and ovarian cancer, died unexpectedly last Sunday.

One of the senior leaders at Dana-Farber during his nearly half century of work there, Livingston was credited with shedding light on the genes that regulate cell growth, with insights into inherited BRCA1 and BRCA2 mutations that helped lay the scientific foundation for targeted therapies and earlier detection that have transformed the field.

How to col­lect and sub­mit RWD to win ap­proval for a new drug in­di­ca­tion: FDA spells it out in a long-await­ed guid­ance

Real-world data is messy. There can be differences in the standards used to collect different types of data, differences in terminologies and curation strategies, and even in the way data is exchanged.

While acknowledging this somewhat controlled chaos, the FDA is now explaining how biopharma companies can submit study data derived from real-world data (RWD) sources in applicable regulatory submissions, including new drug indications.

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Leen Kawas (L) has resigned as CEO of Athira and will be replaced by COO Mark Litton

Ex­clu­sive: Athi­ra CEO Leen Kawas re­signs af­ter in­ves­ti­ga­tion finds she ma­nip­u­lat­ed da­ta

Leen Kawas, CEO and founder of the Alzheimer’s upstart Athira Pharma, has resigned after an internal investigation found she altered images in her doctoral thesis and four other papers that were foundational to establishing the company.

Mark Litton, the company’s COO since June 2019 and a longtime biotech executive, has been named full-time CEO. Kawas, meanwhile, will no longer have ties to the company except for owning a few hundred thousand shares.

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David Lockhart, ReCode Therapeutics CEO

Pfiz­er throws its weight be­hind LNP play­er eye­ing mR­NA treat­ments for CF, PCD

David Lockhart did not see the meteoric rise of messenger RNA and lipid nanoparticles coming.

Thanks to the worldwide fight against Covid-19, mRNA — the genetic code that can be engineered to turn the body into a mini protein factory — and LNPs, those tiny bubbles of fat carrying those instructions, have found their way into hundreds of millions of people. Within the biotech world, pioneers like Alnylam and Intellia have demonstrated just how versatile LNPs can be as a delivery vehicle for anything from siRNA to CRISPR/Cas9.

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No­vo CEO Lars Fruer­gaard Jør­gensen on R&D risk, the deal strat­e­gy and tar­gets for gen­der di­ver­si­ty

 

I kicked off our European R&D summit last week with a conversation involving Novo Nordisk CEO Lars Fruergaard Jørgensen. Novo is aiming to launch a new era of obesity management with a new approval for semaglutide. And Jørgensen had a lot to say about what comes next in R&D, how they manage risk and gender diversity targets at the trendsetting European pharma giant.

John Carroll: I’m here with Lars Jørgensen, the CEO of Novo Nordisk. Lars, it’s been a really interesting year so far with Novo Nordisk, right? You’ve projected a new era of growing sales. You’ve been able to expand on the GLP-1 franchise that was already well established in diabetes now going into obesity. And I think a tremendous number of people are really interested in how that’s working out. You have forecast a growing amount of sales. We don’t know specifically how that might play out. I know a lot of the analysts have different ideas, how those numbers might play out, but that we are in fact embarking on a new era for Novo Nordisk in terms of what the company’s capable of doing and what it’s able to do and what it wants to do. And I wanted to start off by asking you about obesity in particular. Semaglutide has been approved in the United States for obesity. It’s an area of R&D that’s been very troubled for decades. There have been weight loss drugs that have come along. They’ve attracted a lot of attention, but they haven’t actually ever gained traction in the market. My first question is what’s different this time about obesity? What is different about this drug and why do you expect it to work now whereas previous drugs haven’t?

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Pascal Soriot, AstraZeneca CEO (via Getty images)

UP­DAT­ED: FDA slaps As­traZeneca's MCL-1 can­cer drug with a hold af­ter safe­ty is­sue — 2 years af­ter Am­gen axed a trou­bled ri­val

There are new questions being posed about a class of cancer drugs in the wake of the second FDA-enforced clinical hold in the field.

Two years after the FDA hit Amgen with a clinical hold on its MCL-1 inhibitor AMG 397 following signs of cardiac toxicity, AstraZeneca says that regulators hit them with a hold on their rival therapy of the same class.

The pharma giant noted on clinicaltrials.gov that its Phase I/II study for the MCL-1 drug AZD5991 “has been put on hold to allow further evaluation of safety related information.”

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Sur­geons suc­cess­ful­ly at­tach pig kid­ney to a hu­man for the first time, us­ing tech from Unit­ed's Re­vivi­cor

In a first, researchers reportedly successfully transplanted a pig kidney into a human without triggering an immediate immune response this week. And the technology came from the biotech United Therapeutics.

Surgeons spent three days attaching the kidney to the patient’s blood vessels, but when all was said and done, the kidney appeared to be functioning normally in early testing, Reuters and the New York Times were among those to report. The kidney came from a genetically altered pig developed through United’s Revivicor unit.

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Sen. Richard Durbin (D-IL, foreground) and Sen. Richard Blumenthal (D-CT) (Patrick Semansky/AP Images)

Sen­a­tors back FDA's plan to re­quire manda­to­ry pre­scriber ed­u­ca­tion for opi­oids

Three Senate Democrats are backing an FDA plan to require mandatory prescriber education for opioids as overdose deaths have risen sharply over the past decade, with almost 97,000 American opioid-related overdose deaths in the past year alone.

While acknowledging a decline in overall opioid analgesic dispensing in recent years, the FDA said it’s reconsidering the need for mandatory prescriber training through a REMS given the current situation with overdoses, and is seeking input on the aspects of the opioid crisis that mandatory training could potentially mitigate.